list of cocaine analogues
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{{multiple image
| direction = vertical
| footer = Top: Cocaine in the chair conformation of the tropane-ring, with only its tropane locants given.
Middle: Cocaine with its numerical substitution position locants.
2′ (6′) = ortho, 3′ (5′) = meta & 4′ = para
Bottom: Alternate two-dimensional molecular diagram of cocaine; shown specifically as a protonated, NH+, hydrochloride, and disregarding 3D stereochemistry
| image1 = Cocaine positions tropane-ring only.png
| width1 = 250
| image2 = Cocaine positions numbered.PNG
| width2 = 250
| image3 = CocaineHCl.svg
| width3 = 250
}}
This is a list of cocaine analogues. A cocaine analogue is an (usually) artificial construct of a novel chemical compound from (often the starting point of natural) cocaine's molecular structure, with the result product sufficiently similar to cocaine to display similarity in, but alteration to, its chemical function. Within the scope of analogous compounds created from the structure of cocaine, so named "cocaine analogues" retain 3β-benzoyloxy or similar functionality (the term specifically used usually distinguishes from phenyltropanes, but in the broad sense generally, as a category, includes them) on a tropane skeleton, as compared to other stimulants of the kind. Many of the semi-synthetic cocaine analogues proper which have been made & studied have consisted of among the nine following classes of compounds:{{efn|{{cite journal | last1 = Singh | first1 = Satendra |display-authors=etal | year = 2000 | title = Chemistry, Design, and Structure-Activity Relationship of Cocaine Antagonists | url = https://www.erowid.org/archive/rhodium/pdf/cocaineanalogs.pdf | journal = Chem. Rev. | volume = 100 | issue = 3| pages = 925–1024 | doi=10.1021/cr9700538 | pmid=11749256}} ←[https://www.erowid.org/archive/rhodium/pdf/cocaineanalogs.pdf#45 Page #969 (45th page of article)] §III. ¶1. Final line. Last sentence.}}
- stereoisomers of cocaine
- 3β-phenyl ring substituted analogues
- 2β-substituted analogues
- N-modified analogues of cocaine
- 3β-carbamoyl analogues
- 3β-alkyl-3-benzyl tropanes
- 6/7-substituted cocaines
- 6-alkyl-3-benzyl tropanes
- piperidine homologues of cocaine
However strict analogues of cocaine would also include such other potential combinations as phenacyltropanes & other carbon branched replacements not listed above. The term may also be loosely used to refer to drugs manufactured from cocaine or having their basis as a total synthesis of cocaine, but modified to alter their effect & QSAR. These include both intracellular sodium channel blocker anaesthetics and stimulant dopamine reuptake inhibitor ligands (such as certain, namely tropane-bridged-excised, piperidines). Additionally, researchers have supported combinatorial approaches for taking the most promising analogues currently elucidated and mixing them to the end of discovering novel & efficacious compounds to optimize their utilization for differing distinct specified purposes.{{efn| ←[https://www.erowid.org/archive/rhodium/pdf/cocaineanalogs.pdf#94 Page #1,018 (94th page of article) 2nd column, 2nd paragraph.]}}
[[Structural analog#Chemistry|Analogs ''sensu stricto'']]
=Cocaine Stereoisomers=
{{table alignment}}
class="wikitable defaultcenter col3right col4right col5left"
! Structure ! Stereoisomer ! {{verth|va=middle|S. Singh's ! IC50 (nM) |
x100px
|R-cocaine | | 102 | methyl(1R,2R,3S,5S)-3-(benzoyloxy)-8-methyl-8-azabicyclo[3.2.1]octane-2-carboxylate |
x110px
| R-pseudococaine | 172 | 15800 | methyl(1R,2S,3S,5S)-3-(benzoyloxy)-8-methyl-8-azabicyclo[3.2.1]octane-2-carboxylate |
| x110px
| 173 | 6160 | methyl(1R,2R,3R,5S)-3-(benzoyloxy)-8-methyl-8-azabicyclo[3.2.1]octane-2-carboxylate |
x110px
| 174 | 28500 | methyl(1R,2S,3R,5S)-3-(benzoyloxy)-8-methyl-8-azabicyclo[3.2.1]octane-2-carboxylate |
x100px
| 175 | 15800 | methyl(1S,3R,4R,5R)-3-(benzoyl)oxy-8-methyl-8-azabicyclo[3.2.1]octane-4-carboxylate |
x100px
| 176 | 22500 | methyl(1S,3R,4S,5R)-3-(benzoyl)oxy-8-methyl-8-azabicyclo[3.2.1]octane-4-carboxylate |
x110px
| 177 | 9820 | methyl(1S,3S,4R,5R)-3-(benzoyl)oxy-8-methyl-8-azabicyclo[3.2.1]octane-4-carboxylate |
x110px
| 178 | 67700 | methyl(1S,3S,4S,5R)-3-(benzoyl)oxy-8-methyl-8-azabicyclo[3.2.1]octane-4-carboxylate |
File:Cocaine Pharmacophore.svg highlighted.
While it was originally thought that the 2β-carbomethoxy moiety interacted with the DAT through hydrogen bonding, subsequent research has indicated that electrostatic (ionic) interactions are the primary means of interactions with the DAT.{{efn| ←[https://www.erowid.org/archive/rhodium/pdf/cocaineanalogs.pdf#16 Page #940 (16th page of article) underneath Table 8., above §4]}}]]
There are eight stereoisomers of cocaine (excluding mesomers and modifications to the internal portion of the tropane ring).{{efn| ←[https://www.erowid.org/archive/rhodium/pdf/cocaineanalogs.pdf#46 Page #970 (46th page of article)] Table 27. Figure 29.}} Due to the presence of four asymmetric carbon atoms in the 1- & 5- to 8 (N) position bond bridge that could adopt R- & S- configurations, cocaine can be considered to have as many as sixteen stereoisomers. However, geometric constraints imparted by the bridgehead amine allow only eight to be created.
The natural isomerism of cocaine is unstable and prone to epimerization. For example, the end product of cocaine biosynthesis contains an axial C2-carbomethoxy moiety which readily undergoes epimerization to the equatorial position via saponification.
For any 2D structural diagrams where stereochemistry is not indicated, it should be assumed the analogue depicted shares the stereochemical conformation of R-cocaine unless noted otherwise.
=[[Aromatic hydrocarbon|Arene benzene-ring]] 2′, 3′, 4′ (5′ & 6′) position ([[aryl]]) substitutions=
==''para''-substituted benzoylmethylecgonines==
role="presentation" class="wikitable mw-collapsible mw-collapsed"
|+ class="nowrap" | para-substituted benzoylmethylecgonines | ||
183a | 183b | 183c |
---|---|---|
x150px | x150px | x150px |
183d | 4'-Fluorococaine | P-ISOCOC |
x150px | x170px | x140px |
The MAT binding pocket analogous to the lipophilic place on cocaine-like compounds, inclusive of the benzene ring, is approximate to 9 Å in length. Which is only slightly larger than a phenyl ring by itself.{{efn| ←[https://www.erowid.org/archive/rhodium/pdf/cocaineanalogs.pdf#58 Page #982 (58th page of article)]}}
==''meta''-substituted benzoylmethylecgonines==
class="wikitable sortable"
|+Carbon 3′-hydrogen Substitutions (benzene-3′ "meta" substituted benzoyloxytropanes){{efn| ←[https://www.erowid.org/archive/rhodium/pdf/cocaineanalogs.pdf#47 Page #971 (47th page of article)] Figure 30 & Page #971 (47th page of article) Figure 30 & [https://www.erowid.org/archive/rhodium/pdf/cocaineanalogs.pdf#49 Page #973] (49th page of article) Table 28}} ! Structure ! S. Singh's ! 3′=R ! DAT [3H]WIN 35428 ! 5-HTT [3H]Paroxetine ! NET [3H]Nisoxetine ! Selectivity 5-HTT/DAT ! Selectivity NET/DAT | |||||||
(cocaine) | H | 249 ± 37 | 615 ± 120 | 2500 ± 70 | 2.5 | 10.0 | |
rowspan=5|File:184a-b Scaffold.svg | |||||||
184a | I | 325ɑ | - | - | - | - | |
184b | OH | 1183 ± 115 | 793 ± 33 | 3760 ± 589 | 0.7 | 3.2 | |
191 | OBn | - | - | - | - | - | |
(m-Isococ) | NCS | - | - | - | - | - |
- ɑIC50 value for displacement of [3H]cocaine
role="presentation" class="wikitable mw-collapsible mw-collapsed"
|+ class="nowrap" | meta-substituted benzoylmethylecgonines | |||
184a | 184b | m-ISOCOC | C3-Benzyloxycocaine |
---|---|---|---|
x140px | x140px | x140px | x150px |
==''ortho''-substituted benzoylmethylecgonines==
- ɑIC50 value for displacement of [3H]cocaine
role="presentation" class="wikitable mw-collapsible mw-collapsed"
|+ class="nowrap" | ortho-substituted benzoylmethylecgonines | |||
185a | 185b | 185c | 185d |
---|---|---|---|
x150px | x150px | x150px | x150px |
The hydroxylated 2′-OH analogue exhibited a tenfold increase in potency over cocaine.{{efn| ←[https://www.erowid.org/archive/rhodium/pdf/cocaineanalogs.pdf#48 Page #972 (48th page of article)] ¶2, Line 10.}}
==Manifold and termination benzoyloxy phenyl-substitutions==
class="wikitable" | |
Vanillylmethylecgonine | 186b |
---|---|
x150px | x150px |
Multi-substitutions (substitutions of substitutions; e.g. meta- & para-) or manifold ("many-fold") substituted analogues are analogues where more than one modification from the parent molecule takes place (having numerous intermediary constituents). These are created with often surprising structure–activity relationship results extrapolated therefrom. It is even a common case where two separate substitutions can each yield a weaker, lower affinity or even wholly non-efficacious compound respectively; but due to findings that oftentimes, when used together, such two mutually inferior changes being added in tandem to one analogue has the potential to make the resultant derivative display much greater efficacy, affinity, selectivity &/or strength than even the parent compound; which otherwise was compromised by either of those two alternations when made alone.
class="wikitable sortable"
|+Manifold Compositions of Terminating Phenyl Ring Substitutions (Multiple benzene-2′,3′ & 4′ combined substituted benzoyloxytropanes){{efn| ←[https://www.erowid.org/archive/rhodium/pdf/cocaineanalogs.pdf#47 Page #971 (47th page of article)] Figure 30 & Page #971 (47th page of article) Figure 30 & [https://www.erowid.org/archive/rhodium/pdf/cocaineanalogs.pdf#49 Page #973] (49th page of article) Table 28}} ! Structure ! S. Singh's ! ortho-2′=R ! meta-3′=R ! para-4′=R ! DAT [3H]WIN 35428 ! 5-HTT [3H]Paroxetine ! NET [3H]Nisoxetine ! Selectivity 5-HTT/DAT ! Selectivity NET/DAT | |||||||||
x150px | 186 | HO | H | I | 215 ± 19 | 195 ± 10 | 1021 ± 75 | 0.9 | 4.7 |
x70px | (Vanillylmethylecgonine){{cite journal | year = 1984 | title = Hydroxymethoxybenzoylmethylecgonines: New metabolites of cocaine from human urine | pmid = 6708474 | journal = Journal of Analytical Toxicology | volume = 8 | issue = 1| pages = 29–34 | last1 = Smith | first1 = RM | last2 = Poquette | first2 = MA | last3 = Smith | first3 = PJ | doi=10.1093/jat/8.1.29}} | H | OCH3 | OH | - | - | - | - | - |
class="wikitable sortable"
|+Terminating Phenyl Carbon Ring Fusions & Alterations{{efn| ←[https://www.erowid.org/archive/rhodium/pdf/cocaineanalogs.pdf#47 Page #971 (47th page of article)] Figure 30 & Page #971 (47th page of article) Figure 30 & [https://www.erowid.org/archive/rhodium/pdf/cocaineanalogs.pdf#49 Page #973] (49th page of article) Table 28}} ! Structure ! S. Singh's ! C=R ! DAT [3H]Cocaine (IC50) | |||
x150px | 187 | 1-naphthalene | 742 ± 48 |
x150px | 188 | 2-naphthalene | 327 ± 63 |
=Benzoyl and carbomethoxy branch modifications=
{{multiple image
| direction = vertical
| image1 = Spirocyclic cocaine analog.svg
| width1 = 220
| caption1 = Spirocyclic benzoyl branch modification that fits criteria as a cocaine analog and a phenyltropane both (tropane 2nd locant ester rendered in given depiction shows, as has been attested, to only having been successfully alpha configured){{cite journal | last1 = Sakamuri | first1 = Sukumar |display-authors=etal | year = 2000 | title = Synthesis of novel spirocyclic cocaine analogs using the Suzuki coupling | journal = Tetrahedron Letters | volume = 41 | issue = 13| pages = 2055–2058 | doi = 10.1016/S0040-4039(00)00113-1 }}
| image2 = Spirocyclic_cocaine_analog_12.svg
| width2 = 220
}}
- Benzoylthiomethylecgonine{{cite journal | last1 = Isomura | first1 = Shigeki | last2 = Hoffman | first2 = Timothy Z. | last3 = Wirsching | first3 = Peter | last4 = Janda | first4 = Kim D. | year = 2002 | title = Benzoylthio-. cocaine, analogue substitution. Synthesis, Properties, and Reactivity of Cocaine Benzoylthio Ester Possessing the Cocaine Absolute Configuration | journal = J. Am. Chem. Soc. | volume = 124 | issue = 14| pages = 3661–3668 | doi = 10.1021/ja012376y | pmid=11929256}}
A sulfur in place of the oxygen at the benzoyl ester single bond results in a lower electronegativity than that of cocaine.
- Cocaine reverse ester (REC){{cite journal | vauthors = Daum SJ, Martini CM, Kullnig RK, Clarke RL | title = Compounds affecting the central nervous system. I. Tropane-2 ,3 -diol derivatives. A reverse ester of cocaine | journal = The Journal of Organic Chemistry | volume = 37 | issue = 10 | pages = 1665–9 | date = May 1972 | pmid = 5031343 | doi = 10.1021/jo00975a045 }}
REC is a cocaine analogue which contains a "reversed" C2 carbomethoxy moiety. In animal studies, REC lacked cocaine-like stimulant effects.
=C1-tropane-ring hydrogen—substitutions=
{{sort-under}}
- ɑ, P < 0.05 compared with (—)-cocaine (one-way ANOVA followed by Dunnett's multiple comparisons test)
- b, P < 0.01 compared with (—)-cocaine (one-way ANOVA followed by Dunnett's multiple comparisons test)
- cLidocaine was found to have a value of 39.6 ± 2.4, the weakest of all tested.
- dSame reference gives 25.9 ± 2.4 μM for (+)-cocaine and 13.6 ± 1.3 μM for norcocaine. Comparably it gives 12.7 ± 1.5 μM for the sigmaergic affinity of (+)-amphetamine. Another reference gives 1.7-6.7 μM for (—)-cocaine. All values Ki.[http://www.nature.com/npp/journal/v26/n4/full/1395834a.html Involvement of the Sigma1 Receptor in Cocaine-induced Conditioned Place Preference: Possible Dependence on Dopamine Uptake Blockade] Pascal Romieu et al. Neuropsychopharmacology (2002) 26 444-455.10.1038/S0893-133X(01)00391-8
- Using same data-set as above table, the following compounds were found to compare as:
- CFT @ DAT = 39.2 ± 7.1 (n = 5)
- fluoxetine @ SERT = 27.3 ± 9.2 (n = 3)
- desipramine @ NET = 2.74 ± 0.59 (n = 3)
Cocaine analogs substituting the C1-tropane ring position, requiring sulfinimine (N-sulfinyl-imine) chemistry (before the innovation of which were untenable) which bind unlike the typical configuration at DAT (open to out) as cocaine (with its terminal D79-Y156 distance of 6.03 Å), or in the atypical (closed to out) conformation of the benztropines (3.29 Å). Though closer to the open to out: (—)-1-methyl-cocaine = 4.40 Å & (—)-1-phenyl-cocaine = 4.89 Å, and exhibiting preferential interaction with outward facing DAT conformation, they appear to have the lack of behavioral stimulation as-like the closed to out type. Despite having non-stimulant behavior profiles, they still seem to have anti-depressant behavioral profiles.
The C1 phenyl analog is ten times stronger than cocaine as a dopamine reuptake pump ligand, and twenty four times stronger as a local anesthetic (voltage-dependent Na+ channel blocker), whereas the C1 methyl analog is 2.3 times less potent as a local anesthetic.
cf. hydroxytropacocaine for a natural alkaloid (lacking however, the 2-position carbmethoxy) that is a C1 substituent with a hydroxy group.
=2''β''-substitutions=
class="wikitable sortable"
|+Direct 2β Substitutions{{efn| ←[https://www.erowid.org/archive/rhodium/pdf/cocaineanalogs.pdf#49 Page #973 (49th page of article)] §C. & Page #974 (50th page of article) Figure 31 & Page #976 (52nd page of article) Table 29.}} ! Structure ! S. Singh's ! R ! DAT [3H]WIN 35428 ! 5-HTT [3H]Paroxetine ! NET [3H]Nisoxetine ! Selectivity 5-HTT/DAT ! Selectivity NET/DAT | |||||||
rowspan=17|File:Cocaine analog 196a-o.svg | |||||||
(Cocaine) | Me | 89 ± 4.8 | 1045 ± 89 | 3298 ± 293 | 11.7 | 37.0 | |
196a (Cocaethylene) | Et | 195 ± 45 | 5801 ± 493 | 10000 ± 751 | 29.7 | 51.3 | |
196b | n-Pr | 196 ± 46 | 4517 ± 430 | 6124 ± 262 | 23.3 | 31.2 | |
196c | i-Pr | 219 ± 48 | 25224 ± 1498 | 30384 ± 1685 | 115 | 139 | |
196d | Ph | 112 ± 31 | 33666 ± 3330 | 31024 ± 1909 | 300 | 277 | |
196e | Bn | 257 ± 14 | 302 ± 23 | 20794 ± 950 | 1.2 | 80.9 | |
196f | β-phenethyl | 181 ± 10 | 615 ± 52 | 19944 ± 1026 | 3.4 | 110 | |
196g | γ-phenylpropyl | 147 ± 19 | 374 ± 15 | 4893 ± 344 | 2.5 | 33.3 | |
196h | cinnamyl | 371 ± 15 | 368 ± 6.3 | 68931 ± 3476 | 1.0 | 186 | |
196i | p-NO2-β-phenethyl | 601 ± 28 | - | - | - | - | |
196j | p-Cl-β-phenethyl | 271 ± 12 | - | - | - | - | |
196k | p-NH2-β-phenethyl | 72 ± 7 | - | - | - | - | |
196l | p-NCS-β-phenethyl | 196 ± 14 | - | - | - | - | |
196m | p-azido-β-phenethyl | 227 ± 19 | - | - | - | - | |
196n | (p-NHCOCH2Br)β-phenethyl | 61 ± 6 | - | - | - | - | |
196o | (p-NHCO(CH2)2CO2Et)β-phenethyl | 86 ± 4 | - | - | - | - | |
rowspan=5|File:Cocaine analog 197a-d.svg | 197a | NH2 | 753 ± 41.3 | 13725 ± 1256 | 3981 ± 229 | 18.2 | 5.3 |
197b | -NMe2 | 127 ± 6.36 | 143713 ± 8854 | 7329 ± 158 | 1131 | 57.7 | |
197c | -N(OMe)Me | 60 ± 6.4 | 28162 ± 2565 | 3935 ± 266 | 469 | 65.6 | |
197d | -NHMe | 2424 ± 118 | 44798 ± 2105 | 4213 ± 206 | 18.5 | 1.7 | |
197e (Benzoylecgonine) | -OH | 195000 | - | - | - | - | |
rowspan=2|File:Cocaine analog 196-197.svg | 197f | HOCH2- | 561 ± 149 | - | - | - | - |
197g (Tropacocaine) | H | 5180 ± 1160 | - | - | - | - |
role="presentation" class="wikitable mw-collapsible mw-collapsed"
|+ class="nowrap" | 2β-Substituted Analogue Structures | ||||
196a (Cocaethylene) | 196b | 196c | 196d | 196e |
---|---|---|---|---|
x145px | x145px | x145px | x145px | x145px |
196f | 196g | 196h | 196i | 196j |
x165px | x165px | x165px | x165px | x165px |
196k | 196l | 196m | 196n | 196o |
x165px | x165px | x165px | x165px | x165px |
197a | 197b | 197c | 197d | 197e |
x145px | x145px | x145px | x145px | x145px |
197f | 197g | |||
x145px | x145px |
Compounds 196e-h possess greater SERT affinity than cocaine, but possess weaker NET/DAT affinities (with the exception of 196g at NET). Compounds 196k, 196n, 196o, and 197c all possess greater DAT affinity than cocaine. Compound 197b (dimethyl amide) displayed a 1,131-fold increased selectivity in affinity over the serotonin transporter, with only slight reductions in potency for the dopamine & norepinephrine transporters.{{efn| ←[https://www.erowid.org/archive/rhodium/pdf/cocaineanalogs.pdf#50 Page #974 (50th page of article)] Final ¶ (5th), Second line.}} Whereas 197c (Weinreb amide, N-methoxy-N-methyl amide) had a 469× increase at SERT, with greater affinity for DAT than cocaine and an equal NET affinity.{{efn| ←[https://www.erowid.org/archive/rhodium/pdf/cocaineanalogs.pdf#51 Page #975 (51st page of article)] First ¶, first line.}} 197b was 137×, and 196c 27× less potent at binding to the serotonin transporter, but both had a NET / DAT ratio that made for a better dopaminergic than cocaine.{{efn| ←[https://www.erowid.org/archive/rhodium/pdf/cocaineanalogs.pdf#51 Page #975 (51st page of article)] First ¶, 4th line.}} The consideration that large, bulky C2 substituents would alter the spatial conformation of the tropane ring system by distorting the piperidine portion of the system and thus hamper binding{{efn| ←[https://www.erowid.org/archive/rhodium/pdf/cocaineanalogs.pdf#50 Page #974 (50st page of article)] First (left) column, third ¶}} appears to be unfounded.{{efn| ←[https://www.erowid.org/archive/rhodium/pdf/cocaineanalogs.pdf#50 Page #937 (13th page of article)] Second (right) column, first ¶. Above/before §2}}
Benzoylecgonine (197e) is the inactive primary metabolite of cocaine generated through hydrolysis of the C2 methyl ester. In vitro binding studies indicate that benzoylecgonine is ~2,200x less potent than cocaine at the dopamine transporter, possibly due to zwitterion formation preventing strong DAT binding. In contrast to in vitro studies, the lack of activity observed in in vivo studies is likely the result of reduced blood–brain barrier penetration than formation of a zwitterion.{{efn| ←[https://www.erowid.org/archive/rhodium/pdf/cocaineanalogs.pdf#50 Page #974 (50st page of article)] First (left) column, fourth ¶}}
==[[Bioisostere]] 2-position carbmethoxy-ester functional replacements==
class="wikitable sortable"
|+2β-isoxazole and isoxazoline ring containing analogues{{efn| ←[https://www.erowid.org/archive/rhodium/pdf/cocaineanalogs.pdf#50 Page #974 (50th page of article)] Figure 31 & Page #977 (53rd page of article) Table 30.}}{{efn| ←[https://www.erowid.org/archive/rhodium/pdf/cocaineanalogs.pdf#50 Page #974 (50th page of article)] Figure 31 & Page #977 (53rd page of article) Table 30.}}{{efn| ←[https://www.erowid.org/archive/rhodium/pdf/cocaineanalogs.pdf#50 Page #974 (50th page of article)] Figure 31 & Page #977 (53rd page of article) Table 30.}} ! Structure ! S. Singh's ! R ! [3H]Mazindol ! [3H]DA ! Selectivity Uptake/Binding | |||||
(Cocaine) | (H) | 580 ± 70 | 570 ± 180 | 1.0 | |
rowspan=6|File:Cocaine analog 198.svg | |||||
198a | H | 520 ± 40 | 260 ± 70 | 0.5 | |
198b | CO2Et (5′-carboethoxy-) | 120 ± 10 | 290 ± 40 | 2.4 | |
198c | BOC | 2230 ± 220 | 1820 ± 810 | 0.8 | |
198d | Ph | 2000 ± 640 | 2920 ± 1620 | 1.5 | |
198e | CH=CHCO2Me | 3600 ± 400 | 3590 ± 1180 | 1.0 | |
rowspan=3|x140px | |||||
199a | β(or R)CO2Et | 710 ± 150 | 1060 ± 340 | 1.5 | |
199b | α(or S)CO2Et | 5830 ± 630 | 8460 ± 620 | 1.4 | |
x140px | 200 | 880 ± 350 | 400 ± 140 | 0.4 |
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|+ class="nowrap" | 2β-isoxazole and isoxazoline ring containing analogues | |||
198a | 198b | 198c | 198d |
---|---|---|---|
x165px | x165px | x165px | x165px |
198e | 199a | 199b | 200 |
x165px | x165px | x165px | x140px |
==Vinylogous 2''β''-position carbmethoxy-ester functional replacements==
class="wikitable sortable"
|+vinylogous 2β analogues{{efn| ←[https://www.erowid.org/archive/rhodium/pdf/cocaineanalogs.pdf#50 Page #974 (50th page of article)] Figure 31 & Page #977 (53rd page of article) Table 30.}} ! Structure ! S. Singh's ! R ! [3H]Mazindol ! [3H]DA ! Selectivity Uptake/Binding | ||||
rowspan=7|220px | ||||
Cocaine | 580 ± 70 | 570 ± 180 | 1 | |
201a | H | 1730 ± 550 | 1120 ± 390 | 0.6 |
201b | Cl | 222 ± 49 | 368 ± 190 | 1.6 |
201c | CO2Et | 50 ± 10 | 130 ± 10 | 2.6 |
201d | CH=CHCO2Et | 1220 ± 100 | 870 ± 50 | 0.7 |
201e | PO(OEt)2 | 4850 ± 470 | 5500 ± 70 | 1.1 |
role="presentation" class="wikitable mw-collapsible mw-collapsed"
|+ class="nowrap" | Vinylogous 2β analogues | ||||
201a | 201b | 201c | 201d | 201e |
---|---|---|---|---|
x150px | x150px | x150px | x150px | x150px |
Compounds 201b & 201c were significantly more potent than cocaine while compounds 201a, 201d & 201e were significantly less potent. This finding indicates that the presence of a hydrogen bond acceptor (i.e. carbomethoxy) at the 2β position is not absolutely necessary for the creation of high affinity cocaine analogues.{{efn| ←[https://www.erowid.org/archive/rhodium/pdf/cocaineanalogs.pdf#52 Page #976 (52nd page of article)]}}
role="presentation" class="wikitable mw-collapsible mw-collapsed"
|+ class="nowrap" | Miscellaneous 2β-substituted cocaine analogues | ||||
[2H5-phenyl]-cocaine | HPBE | [2H3-N-methyl]-cocaine | C2-ethyl-OSO2CF2 cocaine | 2-[(2-methoxy-2-oxoethoxy)methyl] cocaine |
---|---|---|---|---|
File:D5-phenyl cocaine.svg | File:Hydroxypropyl benzoylecgonine.svg.{{cite journal | title = Comparative Potency for Impulse-Blockade and for Cutaneous Analgesia of Traditional and Novel Local Anesthetics | author = Yoshihiro Hamaya, Hesham Abdelrazek, Gary R. Strichartz | date = 2002 | url = http://www.asaabstracts.com/strands/asaabstracts/abstract.htm?year=2002&index=10&absnum=1331 | quote = Hydroxypropylbenzoylecgonine (HPBE) is the only effective analgesic compound in [Esterom]. | journal = Abstracts of American Society of Anesthesiologists Annual Meeting }}{{Dead link|date=March 2020 |bot=InternetArchiveBot |fix-attempted=yes }}]] | File:D3-methyl cocaine.svg | File:C2-ethyl-OSO2CF2 cocaine Structure.svg | x155px |
=''N''-modifications=
class="wikitable sortable"
|+Nitrogen Substitutions ! Compound ! S. Singh's ! N8-R ! [3H]Mazindol ! [3H]DA ! Selectivity Uptake/Binding | |||||
240px | 217 (Cocaine methiodide)| | ||||
|10700 ± 1530ɑ | - | - | |||
rowspan=17|File:Cocaine analog 219.svg | (Cocaine) | CH3 | 280 ± 60 102ɑ | 320 ± 10 | 1.1 |
218 (Norcocaine) | H | 303 ± 59ɑ | - | - | |
219a | Bn | 668 ± 67ɑ | - | - | |
219b | Ac | 3370 ± 1080ɑ | - | - | |
219c | CH2CH2OH | 700 ± 100 | 1600 ± 200 | 2.3 | |
219d | CH2CO2CH3 | 480 ± 40 | 1600 ± 100 | 3.3 | |
219e | CH2CO2H | 380 ± 20 | 2100 ± 400 | 5.5 | |
220a | SO2CH3 (Ms) | 1290 ± 80 | 1970 ± 70 | 1.5 | |
220b | SO2CF3 (Tf) | 330 ± 30 | 760 ± 20 | 2.3 | |
220c | SO2NCO | 120 ± 10 | 160 ± 10 | 1.3 | |
220d | SO2Ph | 20800 ± 3500 | 61000 | 2.9 | |
220e | SO2C6H4-4-NO2 (nosyl) | 5720 ± 1140 | 18800 ± 90 | 3.3 | |
220f | SO2C6H4-4-OCH3 | 6820 ± 580 | 16400 ± 1400 | 2.4 | |
221a | NO | 99500 ± 12300 | 231700 ± 39500 | 2.3 | |
221b | NO2 | 7500 ± 900 | 21200 ± 600 | 2.8 | |
221c | NHCOCH3 | >1000000 | >1000000 | - | |
221d | NH2 | - | - | - |
- ɑIC50 (nM) for displacement of [3H]WIN 35428
role="presentation" class="wikitable mw-collapsible mw-collapsed"
|+ class="nowrap" | N-Modified Analogue Structures | |||
Norcocaine (218) | 219a | 219b | 219c |
---|---|---|---|
x140px | x140px | x140px | x140px |
219d | 219e | 220a | 220b |
x140px | x140px | x140px | x140px |
220c | 220d | 220e | 220f |
x140px | x140px | x140px | x140px |
221a | 221b | 221c | 221d |
x140px | x140px | x140px | x140px |
role="presentation" class="wikitable mw-collapsible mw-collapsed"
|+ class="nowrap" | Miscellaneous N-modified cocaine analogues | |||
N6 Regioisomer{{US patent|6479509}} | N7 Regioisomer | ortho-Phenyl N7 Regioisomer | 8-Oxa cocaine{{Cite journal | doi = 10.1016/S0960-894X(99)00273-5| pmid = 10406650| title = Synthesis of 8-oxa analogues of norcocaine endowed with interesting cocaine-like activity| journal = Bioorganic & Medicinal Chemistry Letters| volume = 9| issue = 13| pages = 1831–1836| year = 1999| last1 = Kozikowski | first1 = A. P. | last2 = Simoni | first2 = D. | last3 = Roberti | first3 = M. | last4 = Rondanin | first4 = R. | last5 = Wang | first5 = S. | last6 = Du | first6 = P. | last7 = Johnson | first7 = K. M. | doi-access = free }} (cf Meltzer with PTs) |
---|---|---|---|
x140px | x140px | x140px | x140px |
= Tricyclic cocaine analogues =
==8 to 2 tethered analogues==
class="wikitable"
|+Activity at monoamine transporters: Binding Affinities & MAT Inhibition of Bridged Phenyltropanes Ki (nM) {{efn| ←[https://www.erowid.org/archive/rhodium/pdf/cocaineanalogs.pdf#39 Page #964 (39th page of article)] Table 23.}} !Compound !Structure ![3H]Mazindol binding ![3H]DA uptake ![3H]5-HT uptake ![3H]NE uptake !selectivity | ||||||
cocaine | 375 ± 68 | 423 ± 147 | 155 ± 40 | 83.3 ± 1.5 | 0.4 | |
(–)-128 | 54.3 ± 10.2 | 60.3 ± 0.4 | 1.76 ± 0.23 | 5.24 ± 0.07 | 0.03 | |
(+)-128 | 79 ± 19 | 114 ± 28 | 1.48 ± 0.07 | 4.62 ± 0.31 | 0.01 | |
(±)-128 | x140px | 61.7 ± 8.5 | 60.3 ± 0.4 | 2.32 ± 0.23 | 2.69 ± 0.12 | 0.04 |
129 | x140px | 6.86 ± 0.43 | 24.0 ± 1.3 | 1.77 ± 0.04 | 1.06 ± 0.03 | 0.07 |
130a | x140px | 17.2 ± 1.13 | 10.2 ± 1.4 | 78.9 ± 0.9 | 15.0 ± 0.4 | 7.8 |
131a | x140px | 4.00 ± 0.07 | 2.23 ± 0.12 | 14.0 ± 0.6 | 2.99 ± 0.17 | 6.3 |
131b | x110px | 3.61 ± 0.43 | 11.3 ± 1.1 | 25.7 ± 4.3 | 4.43 ± 0.01 | 2.3 |
132a | x160px | 13.7 ± 0.8 | 14.2 ± 0.1 | 618 ± 87 | 3.84 ± 0.35 | 43.5 |
133a | x140px | 149 ± 6 | 149 ± 2 | 810 ± 80 | 51.7 ± 12 | 5.4 |
See N-front & back bridged phenyltropanes.
class="wikitable"
|+Derivations upon fusions of the tropane's nitrogen bridge{{efn| ←[https://www.erowid.org/archive/rhodium/pdf/cocaineanalogs.pdf#56 Page #980 (56th page of article)] Scheme 52.}} ! Compound ! S. Singh's ! [3H]Mazindol ! [3H]DA ! Selectivity Uptake/Binding | ||||
200px | 222 | 44900 ± 6200 | 115000 ± 15700 | 2.6 |
Back-bridged cocaine analogues are considered more akin to untethered cocaine analogs & phenyltropane derivatives (where the nitrogen lone pair is not fixed or constrained) and better mimics their affinities. This is due to when the eighth carbon tropane position is freely rotatable and unbound it preferably occupies the axial position as defining its least energy & most unhindered state. In front-bridged analogs the nitrogen lone pairings rigid fixity makes it reside in an equatorial placing for the piperidine ring-part of the tropane nucleus, pointing to the two-carbon & three methylene unit bridgehead; giving the attested front-bridged cocaine analogues preference for SERT over DAT.{{efn| ←[https://www.erowid.org/archive/rhodium/pdf/cocaineanalogs.pdf#39 Page #963 (39th page of article)] 2nd (right side) column, 2nd paragraph.}}
== 8 to 3 tethered analogues ==
class="wikitable sortable"
! Structure ! Compound ! R ! X ! [3H]DA Uptake ! [3H]5-HT Uptake ! [3H]NE Uptake ! 5-HT/DA Selectivity ! NE/DA Selectivity | ||||||||
Cocaine | 259 ± 19.9 | 155 ± 0.4 | 108 ± 3.5 | 0.60 | 0.42 | |||
rowspan=12| 120px | ||||||||
5a | H | CO2Me | 268 ± 16.6 | 2046 ± 42 | 26.4 ± 1.9 | 7.63 | 0.10 | |
5b | Me | CO2Me | 403 ± 20 | 179 ± 38 | 4.9 ± 0.2 | 0.44 | 0.01 | |
5c | I | CO2Me | 368 ± 1.6 | 29 ± 1.6 | 5 ± 1.3 | 0.08 | 0.01 | |
7 | H | CO2iPr | 428 ± 45.7 | 1150 ± 1.6 | 52.3 ± 12.0 | 2.69 | 0.12 | |
8 | H | CH2OH | ~3000 | ~1000 | ~300 | ~0.33 | ~ 0.1 | |
9 | H | CH2OAc | 610 ± 53 | 1530 ± 150 | 283 ± 16 | 2.51 | 0.46 | |
10 | H | CH2OCOC(CH3)3 | 1020 ± 70 | 168 ± 53.5 | 1180 ± 130 | 0.16 | 1.16 | |
11 | H | CH2OCOPh | 1750 ± 140 | 1.53 ± 0.19 | 894 ± 126 | 0.0009 | 0.51 | |
12 | H | CH2OCO-2-naphthyl | 1678 ± 124 | 169 ± 16 | 1234 ± 166 | 0.10 | 0.74 | |
13 | H | CH2NHCOCH3 | 6140 ± 50 | 13330 ± 3150 | 2430 ± 340 | 2.17 | 0.39 | |
14 | H | CH2NHCO2C(CH3)3 | 2300 ± 380 | 2360 ± 30 | 1700 ± 60 | 1.03 | 0.74 |
class="wikitable sortable"
! Structure ! Compound ! R ! X ! [3H]DA Uptake ! [3H]5-HT Uptake ! [3H]NE Uptake ! DA/5-HT Selectivity ! NE/DA Selectivity | ||||||||
Cocaine | 423 ± 147 | 155 ± 0.4 | 108 ± 3.5 | 2.7 | 0.26 | |||
rowspan=20| 120px | ||||||||
8a | 4-F | CO2Me | 6620 ± 460 | 335 ± 45 | 584 ± 163 | 2.7 | 0.26 | |
8b | 4-Cl | CO2Me | 853 ± 58 | 34.3 ± 2.9 | 208 ± 111 | 24.8 | 0.24 | |
8c | 3-Cl | CO2Me | 7780 ± 1580 | 53.6 ± 17.2 | 231 ± 44 | 145 | 0.03 | |
8d | 4-Br | CO2Me | 495 ± 13 | 11 ± 3 | 178 ± 9 | 45 | 0.36 | |
8e | 4-I | CO2Me | 764 ± 11 | 21.9 ± 0.3 | 213 ± 31 | 34.9 | 0.28 | |
8f | 4-CF3 | CO2Me | N/T | 12.6 ± 0.5 | 1830 ± 211 | N/T | N/T | |
8g | H | CO2Me | 481 ± 11 | 1140 ± 70 | 53 ± 16 | 0.42 | 0.11 | |
8h | 4-Me | CO2Me | 649 ± 2 | 15 ± 0.4 | 146 ± 28 | 43.3 | 0.22 | |
8i | 4-OCH3 | CO2Me | 3130 ± 160 | 56 ± 4 | 187 ± 5 | 55.9 | 0.06 | |
8j | 4-iPr | CO2Me | N/T | 10.2 ± 0.4 | 1110 ± 200 | N/T | N/T | |
8k | 3,4-Cl2 | CO2Me | 1920 ± 260 | 20 ± 1 | 1000 ± 280 | 96 | 0.52 | |
8l | 2,3-Cl2 | CO2Me | 950 ± 107 | 354 ± 188 | 1210 ± 358 | 2.4 | 1.42 | |
8m | 3,5-Cl2 | CO2Me | 5600 ± 400 | 437 ± 0.3 | 4100 ± 500 | 12.8 | 0.73 | |
8n | 3,4-F2 | CO2Me | 7440 ± 19 | 101 ± 8.7 | 394 ± 98 | 73.7 | 0.05 | |
8o | 4-Br-3-Cl | CO2Me | 5420 ± 940 | 2.3 ± 0.1 | 459 ± 80 | 2360 | 0.08 | |
8p | 3-Cl-4-I | CO2Me | 3140 ± 450 | 1.8 ± 0.3 | 272 ± 55 | 1740 | 0.09 | |
8q | 2-Cl-4-I | CO2Me | 6640 ± 2080 | 74 ± 12.2 | 508 ± 21 | 89.7 | 0.08 | |
8r | 3-Cl-4-Me | CO2Me | >10000 | 6.4 ± 1.3 | 198 ± 10 | >1560 | <0.02 | |
8s | 3,4-Me2 | CO2Me | N/T | 10.1 ± 1.1 | 659 ± 128 | N/T | N/T | |
rowspan=5| 120px | ||||||||
8t | 1-Naphthyl | CO2Me | 9720 ± 700 | 121 ± 3 | 5370 ± 580 | 80.3 | 0.55 | |
8u | 2-Naphthyl | CO2Me | 735 ± 235 | 21 ± 9.9 | 157 ± 13 | 35 | 0.21 | |
8v | 1-Pyrenyl | CO2Me | 9920 ± 906 | 860 ± 20.6 | N/T | 11.5 | N/T | |
8w | 9-Phenanthryl | CO2Me | 1640 ± 30 | 233 ± 44 | 13000 ± 1300 | 39.2 | 0.86 |
- "N/T" = "not tested"
=Tropane ring contraction (azabornane) analogues=
class="wikitable sortable"
|+7-Azabicyclo[2.2.1]heptane Derivatives{{efn| ←[https://www.erowid.org/archive/rhodium/pdf/cocaineanalogs.pdf#43 Page #967 (43rd page of article)] §C. & Page #967 (43rd page of article) Table 25 }} ! Structure ! S. Singh's ! DAT | ||
(Cocaine) | 89 ± 4.8 | |
x140px | 155a | 60400 ± 4800 |
x140px | 155b | 96500 ± 42 |
x140px | 155c | 5620 ± 390 |
x140px | 155d | 18900 ± 1700 |
=6/7 tropane position methoxycocaine & methoxypseudococaine analogues=
class="wikitable sortable"
|+Substitutions upon the 6 & 7 positions of the tropane{{efn| ←[https://www.erowid.org/archive/rhodium/pdf/cocaineanalogs.pdf#58 Page #982 (58th page of article)] §G & Page #983 (59th page of article) Figure 36 & Page #984 (60th page of article) Table 35.}} ! Compound ! S. Singh's ! X ! Ki (nM) ! Ki (nM) ! Selectivity Uptake/Binding | |||||
(Cocaine) | 280 ± 60 | 320 ± 10 | 1.1 | ||
(Pseudococaine) | 10400 ± 300 | 13800 ± 1500 | 1.3 | ||
220px | 225a | 2β, 6β-OCH3 | 98000 ± 12000 | 68000 ± 5000 | 0.7 |
220px | 225b | 2α, 6β-OCH3 | 190000 ± 11000 | 510000 ± 110000 | 2.7 |
220px | 225c | 2β, 7β-OCH3 | 4200 ± 100 | 6100 ± 200 | 1.4 |
220px | 225d | 2α, 7β-OCH3 | 45000 ± 5000 | 110000 ± 4000 | 2.4 |
220px | 225e | 2α, 7α-OCH3 | 54000 ± 3000 | 200000 ± 70000 | 3.7 |
=3''β''-position 2′—(6′) & 2''β''-substitution combination analogues=
class="wikitable sortable"
|+4′-Iodococaine-2β-substituted analogues{{efn| ←[https://www.erowid.org/archive/rhodium/pdf/cocaineanalogs.pdf#55 Page #979 (55th page of article)] Table 31.}} ! Compound ! S. Singh's ! 2β-R ! C2′-R ! IC50 (nM) | ||||
rowspan=11|220px | ||||
211a | CH2OH | H | 6214 ± 1269 | |
211b | CH2OCOCH3 | H | 2995 ± 223 | |
211c | CONHCH3 | H | >100000 | |
211d | CO2Et | H | 2031 ± 190 | |
211e | CO2-i-Pr | H | 1377 ± 10 | |
211f | CO2Ph | H | 2019 ± 253 | |
211g | CO2CH2Ph | H | 4602 ± 325 | |
211h | 3-phenyl-1,2,4-oxadiazole | H | 3459 ± 60 | |
211i | CH=CH2 | H | 2165 ± 253 | |
211j | CH2CH3 | H | 2692 ± 486 | |
200px | 212 | CO2-i-Pr | HO | 663 ± 70 4507 ± 13ɑ 34838 ± 796b |
- ɑFor displacement of [3H]paroxetine (5-HTT & NET)
- bFor displacement of [3H]nisoxetine (5-HTT & NET)
role="presentation" class="wikitable mw-collapsible mw-collapsed"
|+ class="nowrap" | 4′-Iodococaine-2β-substituted analogues | ||||
211a | 211b | 211c | 211d | 211e |
---|---|---|---|---|
200px | 200px | 200px | 200px | 200px |
211f | 211g | 211h | 211i | 211j |
200px | 200px | 200px | 200px | 200px |
=3''β''-Carbamoyl analogues=
class="wikitable sortable"
|+3-position carbamoyl linkage substituting benzoyloxy analogues{{efn| ←[https://www.erowid.org/archive/rhodium/pdf/cocaineanalogs.pdf#57 Page #981 (57th page of article)] §E & Page #982 (58th page of article) Table 33.}} ! Compound ! S. Singh's ! X ! IC50 (nM) ! IC50 (nM) ! Selectivity | |||||
(Cocaine) | (H) | 70 ± 10 | 210 ± 70 | 3.0 | |
rowspan=6|x120px | |||||
223a | H | 5600 ± 700 | 52600 ± 3000 | 9.4 | |
223b | 4-NO2 | 1090 ± 250 | 5700 ± 1200 | 5.2 | |
223c | 4-NH2 | 63300 ± 12200 | >100000 | - | |
223d | 4-N3 | 1000 ± 240 | 1180 ± 360 | 1.2 | |
223e | 4-NCS | 260 ± 60 | 490 ± 80 | 1.9 | |
rowspan=5|x120px | |||||
223f | 3-NO2 | 37 ± 10 | 178 ± 23 | 4.8 | |
223g | 3-NH2 | 2070 ± 340 | 23100 ± 900 | 11.1 | |
223h | 3-N3 | 630 ± 150 | 3900 ± 1590 | 6.2 | |
223i | 3-NCS | 960 ± 210 | 4900 ± 420 | 5.1 |
role="presentation" class="wikitable mw-collapsible mw-collapsed"
|+ class="nowrap" | 3β-Carbamoyl analogues | ||
223a | 223b | 223c |
---|---|---|
x160px | x160px | x160px |
223d | 223e | 223f |
x160px | x160px | x160px |
223g | 223h | 223i |
x160px | x160px | x160px |
=Phenyl 3-position linkage substitutions=
File:Phenyltropane.gif) rendering of Troparil: A structural analogue of cocaine with omitted -COO- linkage – a parent compound of many MAT ligands; those of the phenyltropane class. (Here it is depicted in an unfavourable conformation of the O-Me; The methyl has to be at the other oxygen and trans to optimize its functional stimulation.)]]
{{multiple image
| align = left
| direction = vertical
| footer = The top image above is a 2-Dimensional emulation of the orientation for the animated 3D image to the far right, with a methoxy that is distal from the phenyl group and cis. While the alternate image below that to its bottom shown above is one with the carboxyl methyl group proximal to the phenyl, in its optimum conformation, with a likewise optimum trans configuration.
| image1 = Troparil w ph distal cis OMe.png
| width1 = 190
| image2 = Troparil w ph proximal trans OMe.png
| width2 = 200
}}
See: List of phenyltropanes (Many phenyltropanes are derived from cocaine metabolites, such as methylecgonidine, as precursors. Whereas fully synthetic methods have been devised from the starting material of vinylcarbenoids & pyrroles.){{cite journal | pmid = 8420793 | volume=244 | issue=1 | title=Novel 2-substituted cocaine analogs: binding properties at dopamine transport sites in rat striatum | year=1993 | journal=Eur. J. Pharmacol. | pages=93–7 | last1 = Davies | first1 = HM | last2 = Saikali | first2 = E | last3 = Sexton | first3 = T | last4 = Childers | first4 = SR | doi=10.1016/0922-4106(93)90063-f}}
The difference in the length of the benzoyloxy and the phenyl linkage contrasted between cocaine and phenyltropanes makes for a shorter distance between the centroid of the aromatic benzene and the bridge nitrogen of the tropane in the latter PTs. This distance being on a scale of 5.6 Å for phenyltropanes and 7.7 Å for cocaine or analogs with the benzoyloxy intact.{{efn| ←[https://www.erowid.org/archive/rhodium/pdf/cocaineanalogs.pdf#46 Page #970 (46th page of article)] §B, 10th line}} This may account for PTs increased behavioral stimulation profile over cocaine.{{efn| ←[https://www.erowid.org/archive/rhodium/pdf/cocaineanalogs.pdf#47 Page #971 (47th page of article)] 1st ¶, 10th line}} Differences in binding potency have also been explained considering solvation effects; cocaine containing 2β,3β-ester groups being calculated as more solvated than the WIN-type compounds (i.e. troparil). Higher pKɑs of the tropane nitrogen (8.65 for cocaine, 9.55 for troparil & 11.95 for vinyl analogue 43a), decreased aqueous solvation & decreased conformational flexibility added to increased binding affinity.{{efn| ←[https://www.erowid.org/archive/rhodium/pdf/cocaineanalogs.pdf#25 Page #949 (25th page of article)] 3rd ¶, 20th line}}
Despite the observation of increased stimulation, phenyltropanes lack the local anesthetic sodium channel blocking effect that the benzoyloxy imparts to cocaine. Beside topical affect, this gives cocaine an affinity for binding to sites on the dopamine and serotonin sodium dependent transport areas that are distinct & specific to MAT in contrast to the general sodium channels; creating a separate mechanism of relational affinity to the transporters in addition to its inhibition of the reuptake for those transporters; this is unique to the local anesthetic value in cocaine & analogues with a similar substitute for the benzoyloxy that leaves the sodium channel blockage ability intact. Rendering such compounds as different functionally in their relation to MAT contrasted to phenyltropane analogues which have the local anesthetic bridge removed.{{cite web|url=http://www.drugbank.ca/drugs/DB00907 |title=Drugbank website "drug card", "(DB00907)" for Cocaine: Giving ten targets of the molecule in vivo, including dopamine/serotonin sodium channel affinity & K-opioid affinity |publisher=Drugbank.ca |accessdate=9 March 2010}} (Requiring some of the sodium ions to be pumped from the axon via Na+/K+-ATPase). In addition, it even has been postulated that a crucial role regarding the electron energy imparted via voltage sensitization (and thus action potential blockage with a molecule capable of intersecting its specific channel, in the case of cocaine a sodium channel, that potentially serves in re-quantifying its charge) upon a receptor binding site may attenuate the mediating influence of the inhibitory regulation that autoreceptors play by their slowing neurotransmitter release when an efflux is created through an instance of agonism by a compound; allowing said efflux to be continued without the body's attempt to maintain homeostasis enacting in as readily responsive a manner to its conformational change.{{cite journal | last1 = Sahlholm | first1 = Kristoffer | last2 = Nilsson | first2 = Johanna | last3 = Marcellino | first3 = Daniel | last4 = Fuxe | first4 = Kjell | last5 = Århem | first5 = Peter | year = 2012 | title = Voltage sensitivities and deactivation kinetics of histamine H3 and H4 receptors | journal = Biochimica et Biophysica Acta (BBA) - Biomembranes | volume = 1818 | issue = 12| pages = 3081–3089 | doi = 10.1016/j.bbamem.2012.07.027 | pmid = 22885137 | doi-access = free }} ...Agonist potency at some neurotransmitter receptors has been shown to be regulated by voltage, a mechanism which has been suggested to play a crucial role in the regulation of neurotransmitter release by inhibitory autoreceptors...
class="wikitable"
|+ Various phenyltropane examples |
{{clear}}
=3''β''-Alkylphenyltropane & 3''β''-Alkenyl analogues=
class="wikitable sortable"
|+3-position alkylphenyl linkage substituting benzoyloxy analogues{{efn| ←[https://www.erowid.org/archive/rhodium/pdf/cocaineanalogs.pdf#58 Page #982 (58th page of article)] §F, Table 34 & Figure 35.}} ! Compound ! S. Singh's ! n ! IC50 (nM) ! IC50 (nM) ! Selectivity | |||||
(Cocaine) | 101 ± 26 | 209 ± 20 | 2.1 | ||
rowspan=4|x140px | |||||
224a | 1 | 885 ± 18 | 1020 ± 52 | 1.1 | |
224b | 2 | 9.9 ± 0.33 | 70.5 ± 1.0 | 7.1 | |
224c | 3 | 344 ± 12 | 2680 ± 190 | 7.8 | |
224d | 71.6 ± 0.7 | 138 ± 9 | 1.9 | ||
224e | 2.10 ± 0.04 | 5.88 ± 0.09 | 2.8 |
role="presentation" class="wikitable mw-collapsible mw-collapsed"
|+ class="nowrap" | 3β-Alkylphenyltropane & 3β-Alkenyl analogues | ||||
224a | 224b | 224c | 224d | 224e |
---|---|---|---|---|
x140px | x120px | x140px | | x140px | x120px |
The compound 224e, the 3β-styrene analogue, had the highest potency in its group. While 224b & 224c showed the most selectivity, with 224b having a ten-fold greater potency for the dopamine transporter than cocaine.{{efn| ←[https://www.erowid.org/archive/rhodium/pdf/cocaineanalogs.pdf#58 Page #982 (58th page of article)] 3rd ¶, lines 2, 5 & 6.}}
=6-Alkyl-3-benzyltropane analogues=
class="wikitable"
|+6-Alkyl-3-benzyl-2[(methoxycarbonyl)methyl]tropane analogues{{efn| ←[https://www.erowid.org/archive/rhodium/pdf/cocaineanalogs.pdf#60 Page #984 (60th page of article)] Figure 37.}} ! Sub-category ! a ! b ! c ! d ! e ! f | |||||
rowspan=2|2β,6α-isomers: (229a—f) | |||||
x120px | x120px | x120px | x120px | x120px | x120px |
rowspan=2|2α,6α-isomers: (230a—f) | |||||
x110px | x110px | x110px | x120px | x120px | x120px |
rowspan=2|2β,6β-isomers: (231a—f) | |||||
x110px | x110px | x110px | x100px | x100px | x100px |
rowspan=2|2α,6β-isomers: (232a—f) | |||||
x110px | x110px | x110px | x100px | x90px | x100px |
class="wikitable sortable"
|+6-Alkyl-3-benzyl-2[(methoxycarbonyl)methyl]tropane analogues{{efn| ←[https://www.erowid.org/archive/rhodium/pdf/cocaineanalogs.pdf#60 Page #984 (60th page of article)] §H, Figure 37 & Page #985 (61st page of article) Table 36.}} ! Compound ! S. Singh's ! R ! Ki (nM) ! IC50 (nM) ! Selectivity uptake/binding | |||||
Cocaine | 32 ± 5 338 ± 221 | 405 ± 91 405 ± 91 | 12.6 1.2 | ||
WIN 35065-2 | 33 ± 17 314 ± 222 | 373 ± 10 | 11.3 | ||
rowspan=8| File:229 Analogue Scaffold.svg | |||||
(−)-229a | H | 33 ± 5 | 161 ± 100 | 4.9 | |
229a | H | 91 ± 10 | 94 ± 26 | 1.0 | |
229b | Me | 211 ± 23 | - | - | |
229c | Et | 307 ± 28 | - | - | |
229d | n-Pr | 4180 ± 418 | - | - | |
229e | n-Bu | 8580 ± 249 | - | - | |
229f | Bn | 3080 ± 277 | - | - | |
rowspan=8| File:230 Analogue Scaffold.svg | |||||
(+)-230a | H | 60 ± 6 | 208 ± 63 | 3.5 | |
230a | H | 108 ± 14 | 457 ± 104 | 4.2 | |
230b | Me | 561 ± 64 | - | - | |
230c | Et | 1150 ± 135 | - | - | |
230d | n-Pr | 7240 ± 376 | - | - | |
230e | n-Bu | 19700 ± 350 | - | - | |
230f | Bn | 7590 ± 53 | - | - | |
rowspan=5| File:231 Analogue Scaffold.svg | |||||
231b | Me | 57 ± 5 | 107 ± 36 | 1.9 | |
231c | Et | 3110 ± 187 | - | - | |
231d | n-Pr | 5850 ± 702 | - | - | |
231f | Bn | 1560 ± 63 | - | - | |
rowspan=5| File:232 Analogue Scaffold.svg | |||||
232b | Me | 294 ± 29 | 532 ± 136 | 1.8 | |
232c | Et | 6210 ± 435 | - | - | |
232d | n-Pr | 57300 ± 3440 | - | - | |
232f | Bn | 3080 ± 277 | - | - | |
241 | Bn | 4830 ± 434 | - | - |
class="wikitable mw-collapsible"
|+{{nowrap|Benzylidene derivatives of 6-alkyl-3-benzyltropanes{{efn| ←[https://www.erowid.org/archive/rhodium/pdf/cocaineanalogs.pdf#60 Page #984 (60th page of article)] Scheme 56.}}}} ! Sub-category ! a ! b ! c ! d ! e ! f | |||||
rowspan=2|6α-isomers: (237a—f) | |||||
x95px | x105px | x110px | x125px | x135px | x135px |
rowspan=2|6β-isomers (exo): (238a—f) | |||||
x77px | x85px | x85px | x85px | x85px | x105px |
rowspan=2|3β-benzyl derivatives: (239a—f) | |||||
x115px | x110px | x110px | x130px | x135px | x135px |
rowspan=2|intermediate alkylidene esters: (240a—f) | |||||
x115px | x115px | x115px | x130px | x135px | x135px |
N.B. The benzylidene derivatives serve as synthetic intermediates for 6-Alkyl-3-benzyltropanes and have not been assayed for biological activity. Compounds 237a and 238a are the same compound as both are the parent for either series with a hydrogen saturated in their respective substitution place.
=Direct 2,3-pyrimidino fused=
{{multiple image
| align = center
| direction = vertical
| image1 = Strobamine.svg
| width1 = 280
| caption1 = above: Strobamine, a DARI functional cocaine analog with structural semblance.[http://www.arkat-usa.org/get-file/36494/ Enantioselective synthesis of strobamine and its analogues] Xing Zhang et al. Center for Organic and Medicinal Chemistry, Research Triangle Institute. Issue in Honor of Prof. James M.Cook ARKIVOC 2010 (iv)96-103 Compare the phenyltropane length tropane C2 & C3 functional group fusion variant.[https://books.google.com/books?id=rjtEwOFM5owC&dq=Strobamine&pg=PA17 The Alkaloids; Vol. 44, Geoffrey Cordell]
below: Chalcostrobamine
| image2 = Chalcostrobamine Structure.svg
| width2 = 190
}}
cf. strobamine (at right) for a more efficacious compound as like the below.
class="wikitable sortable" style="margin: auto; border: none;"
|+2,3-direct fused "di-hetero-benzene" rigidified cocaine analogs.{{cite journal|last1=Appell|first1=Michael|last2=Dunn|first2=William J.|last3=Reith|first3=Maarten E.A.|last4=Miller|first4=Larry|last5=Flippen-Anderson|first5=Judith L.|title=An Analysis of the Binding of Cocaine Analogues to the Monoamine Transporters Using Tensor Decomposition 3-D QSAR|journal=Bioorganic & Medicinal Chemistry|volume=10|issue=5|year=2002|pages=1197–1206|issn=0968-0896|doi=10.1016/S0968-0896(01)00389-3|pmid=11886784}} ! Structure ! alphanumeric ! R1 ! R2 ! hDAT ! hSERT ! hNET | ||||||
rowspan=3|230px | ||||||
(−)-3a | H | C6H5 | 58,300 (20,200) | 6140 (3350) | {{NA|NA}} | |
(+)-3a | H | C6H5 | 48,700 (20,100) | 6030 (3400) | {{NA|NA}} | |
rowspan=3|190px | ||||||
(−)-3b | H | NH2 | {{NA|NA}} | {{NA|NA}} | {{NA|NA}} | |
(+)-3b | H | NH2 | {{NA|NA}} | {{NA|NA}} | {{NA|NA}} | |
rowspan=3|190px | ||||||
(−)-3c | H | CH3 | {{NA|NA}} | {{NA|NA}} | {{NA|NA}} | |
(+)-3c | H | CH3 | {{NA|NA}} | {{NA|NA}} | {{NA|NA}} | |
rowspan=3|150px | ||||||
(−)-3d | H | H | {{NA|NA}} | {{NA|NA}} | {{NA|NA}} | |
(+)-3d | H | H | {{NA|NA}} | {{NA|NA}} | {{NA|NA}} | |
240px | (+/—)-3e | C6H5 | C6H5 | 30,000 (11,200) | 3650 (1700) | {{NA|NA}} |
- "NA" = "no affinity", e.g. unquantifiable.
Direct di-hetero-benzene (pyrimidino) 2,3-fused and thus rigidified cocaine analogs.
=Piperidine cocaine-homologues=
class="wikitable sortable"
|+Binding potency of piperidine homologues for displacement of [3H]WIN 35428{{efn| ←[https://www.erowid.org/archive/rhodium/pdf/cocaineanalogs.pdf#62 Page #986 (62nd page of article)] §I, Table 37 & Scheme 58}} ! Compound ! S. Singh's ! 2β-R ! IC50 (nM) | |||
(Cocaine) | CO2CH3 (i.e. CO2Me) | 249 ± 37 | |
x150px | 183a | CO2CH3 | 2522 ± 4 |
x120px | 242 | H | 11589 ± 4 |
x160px | 243 | CO2CH3 | 8064 ± 4 |
cf. phenyltropane piperidine-homologues for compounds with a more optimized conformation that yield higher affinities when binding to MAT.
=Cocaine [[hapten]] analogues=
- ɑ6-(2R,3S)-3-(benzoyloxy)-8-methyl-8-azabicyclo
[3.2.1] octane-2-carbonyloxy-hexanoic acid - b6-(2R,3S)-3-(benzoyloxy)-8-methyl-8-azabicyclo
[3.2.1] octane-2-carboxamido-hexanoic acid
File:Cocaine analog 400 intermediate.svg
class="wikitable sortable"
|+Cocaine transition state analogues (TSAs) which generate catalytic antibodies{{efn| ←[https://www.erowid.org/archive/rhodium/pdf/cocaineanalogs.pdf#92 Page #1,016 (92nd page of article)] Figure 60.}} ! Compound ! S. Singh's ! R | |
rowspan=8|200px | |
401a | CH3 |
401b | (CH2)5CO2H |
401c | CH2CO2H |
401d | COCH2CH2CO2H |
401e | H |
401f | CH2CH2Br |
385g | (CH2)2NHCO(CH2)2CONH2 |
rowspan=6|200px | |
402a | O(CH2)4NHCO(CH2)2CO2N(CO2)2C6H4 |
402b | OH |
402c | O(CH2)2(p-NH2C6H4) |
402d | NH(CH2)5CO2H |
402e | O(CH2)4NHCO(CH2)2CONH2 |
rowspan=5|220px | |
403a | NH2 |
403b | NHCOCH2Br |
403c | NHCO(CH2)3CO2H |
403d | (CH2)3NHCO(CH2)2CONH2 |
Cocaine haptens that create catalytic anti-bodies require transitional states as affected in vivo. Monoclonal antibodies generated against BSA-coupled 402e accelerated the rate of cocaine hydrolysis by ~23,000x and eliminated the reinforcing effects of cocaine administration in rats.[https://patents.google.com/patent/US6566084 Catalytic antibodies against cocaine and methods of using and producing same] Google patents US 6566084 B1{{cite journal|last1=Deng|first1=Shixian|last2=Bharat|first2=Narine|last3=de Prada|first3=Paloma|last4=Landry|first4=Donald W.|title=Substrate-assisted antibody catalysis|journal=Organic & Biomolecular Chemistry|volume=2|issue=3|year=2004|pages=288–90|issn=1477-0520|doi=10.1039/b314264g|pmid=14747854}}{{cite journal |last1=Yang |first1=G. |last2=Chun |first2=J. |last3=Arakawa-Uramoto |first3=H. |last4=Wang |first4=X. |last5=Gawinowicz |first5=M. A. |last6=Zhao |first6=K. |last7=Landry |first7=D. W. |title=Anti-Cocaine Catalytic Antibodies: A Synthetic Approach to Improved Antibody Diversity |journal=Journal of the American Chemical Society |date=1 January 1996 |volume=118 |issue=25 |pages=5881–5890 |doi=10.1021/ja953077}}{{cite journal |last1=Mets |first1=B. |last2=Winger |first2=G. |last3=Cabrera |first3=C. |last4=Seo |first4=S. |last5=Jamdar |first5=S. |last6=Yang |first6=G. |last7=Zhao |first7=K. |last8=Briscoe |first8=R. J. |last9=Almonte |first9=R. |last10=Woods |first10=J. H. |last11=Landry |first11=D. W. |title=A catalytic antibody against cocaine prevents cocaine's reinforcing and toxic effects in rats |journal=Proceedings of the National Academy of Sciences |date=18 August 1998 |volume=95 |issue=17 |pages=10176–10181 |doi=10.1073/pnas.95.17.10176|pmid=9707620 |pmc=21481 |bibcode=1998PNAS...9510176M |doi-access=free }}
Structural/Functional intermediate analogues
=Piperidine Analogues=
- JZ-IV-10 (a "Modafinil hybrid" with nocaine.{{cite journal|last1=Zhou|first1=Jia|last2=He|first2=Rong|last3=Johnson|first3=Kenneth M.|last4=Ye|first4=Yanping|last5=Kozikowski|first5=Alan P.|title=Piperidine-Based Nocaine/Modafinil Hybrid Ligands as Highly Potent Monoamine Transporter Inhibitors: Efficient Drug Discovery by Rational Lead Hybridization|journal=Journal of Medicinal Chemistry|volume=47|issue=24|year=2004|pages=5821–5824|issn=0022-2623|doi=10.1021/jm040117o|pmid=15537337|pmc=1395211}} cf. List of modafinil analogues)
A somewhat recent occurrence among tentative modern folklore which has traversed the circling of rumors mostly confined to the likes of universities and popular culture trivia has been that cocaine is one element, or molecule increment of weight or charge etc., away from the molecular structure of sugar.[http://skeptics.stackexchange.com/questions/20216/is-sugar-one-element-away-from-cocaine-or-any-other-drug Skeptics Stack Exchange: Is sugar one element away from cocaine (or any other drug?)] Though such a statement is false as a general pretense, there is a dextrose based super-structure that has a vaguely similar overlay with cocaine which is "benzoyl-beta-D-glucoside."
=Benztropine (3α-Diphenylmethoxy Tropane) Analogues=
class="wikitable sortable"
|+3α-Diphenylmethoxy tropanes ! Compound ! S. Singh's ! R ! R′ ! Ki (nM) ! IC50 (nM) uptake ! Selectivity uptake/binding | ||||||
(Cocaine) | 388 ± 47 | - | - | |||
(GBR 12909) | 11.6 ± 31 | - | - | |||
rowspan=29|200px | ||||||
(Benztropine) | H | H | 118 ± 9 | 403 ± 115 | 3.4 | |
249a | 4′-F | H | 32.2 ± 10 | 48 | 1.5 | |
249b (AHN 1-055) | 4′-F | 4′-F | 11.8 ± 1 | 71 | 6.0 | |
249c | 3′,4′-di-F | H | 27.9 ± 11 | 181 ± 45.7 | 6.5 | |
249d | 4′-Cl | H | 30.0 ± 12 | 115 | 3.8 | |
249e | 4′-Cl | 4′-Cl | 20.0 ± 14 | 75 | 3.8 | |
249f | 3′,4′-di-Cl | H | 21.1 ± 19 | 47 | 2.2 | |
249g | 3′,4′-di-Cl | F | 18.9 ± 14 | 24 | 1.3 | |
249h | 4′-Br | H | 37.9 ± 7 | 29 | 0.8 | |
249i | 4′-Br | 4′-Br | 91.6 | 34 | 0.4 | |
249j | 4′-NO2 | H | 197 ± 8 | 219 | 1.1 | |
249k | 4′-CN | H | 196 ± 9 | 222 | 1.1 | |
249l | 4′-CF3 | H | 635 ± 10 | 2155 | 3.4 | |
249m | 4′-OH | H | 297 ± 13 | 677 | 2.3 | |
249n | 4′-OMe | H | 78.4 ± 8 | 468 | 6.0 | |
249o | 4′-OMe | 4′-OMe | 2000 ± 7 | 2876 | 1.4 | |
249p | 4′-Me | H | 187 ± 5 | 512 | 2.7 | |
249q | 4′-Me | 4′-Me | 420 ± 7 | 2536 | 6.0 | |
249r | 4′-Et | H | 520 ± 8 | 984 | 1.9 | |
249s | 4′-t-Bu | H | 1918 | 4456 | 2.3 | |
250a | 3′-F | H | 68.5 ± 12 | 250 ± 64.7 | 3.6 | |
250b | 3′-F | 3′-F | 47.4 ± 1 | 407 ± 63.9 | 8.6 | |
250c | 3′-Cl | H | 21.6 ± 7 | 228 ± 77.1 | 10.5 | |
250d | 3′-CF3 | H | 187 ± 5 | 457 ± 72.0 | 2.4 | |
251a | 2′-F | H | 50.0 ± 12 | 140 ± 17.2 | 2.8 | |
251b | 2′-Cl | H | 228 ± 9 | 997 ± 109 | 4.4 | |
251c | 2′-Me | H | 309 ± 6 | 1200 ± 1.64 | 3.9 | |
251d | 2′-NH2 | H | 840 ± 8 | 373 ± 117 | 0.4 |
class="wikitable sortable"
|+3α-Diphenylmethoxy-2β-carbomethoxybenztropine ! Compound ! S. Singh's ! R ! R′ ! IC50 (nM) ! IC50 (nM) ! Selectivity | ||||||
(benztropine) | 312 ± 1.1 | 24100 ± 14800 | 77.2 | |||
(WIN 35428) | 12.9 ± 1.1 | 160 ± 20 | 12.4 | |||
R-256 | 2040 ± 283 | 1460 ± 255 | 0.7 | |||
rowspan=13|200px | ||||||
S-257a | H | H | 33.5 ± 4.5 | 10100 ± 1740 | 301 | |
S-257b | H | F | 13.2 ± 1.9 | 4930 ± 1200 | 373 | |
S-257c (difluoropine) | F | F | 10.9 ± 1.2 | 3530 ± 1480 | 324 | |
S-257d | H | Cl | 15.8 ± 0.95 | 5960 ± 467 | 377 | |
S-257e | Cl | Cl | 91.4 ± 0.85 | 3360 ± 1480 | 36.8 | |
S-257f | H | Br | 24.0 ± 4.6 | 5770 ± 493 | 240 | |
S-257g | Br | Br | 72.0 ± 3.65 | 2430 ± 339 | 33.7 | |
S-257h | H | I | 55.9 ± 10.3 | 9280 ± 1640 | 166 | |
S-257i | Br | I | 389 ± 29.4 | 4930 ± 82 | 12.7 | |
S-257j | I | I | 909 ± 79 | 8550 ± 442 | 9.4 | |
S-257k | H | Me | 49.5 ± 6.0 | 13200 | 266 | |
S-257l | Me | Me | 240 ± 18.4 | 9800 ± 2680 | 40.8 |
class="wikitable sortable"
|+N-Modified 2-carbomethoxybenztropines ! Compound ! S. Singh's ! R ! n ! IC50 (nM) ! IC50 (nM) ! Selectivity | ||||||
rowspan=7|300px | ||||||
258a | 20.3 ± 3.5 | - | - | |||
258b | H | 1 | 223 ± 53 | 4970 ± 700 | 22.3 | |
258c | H | 3 | 22.0 ± 11.9 | 19.7 ± 3 | 0.9 | |
258d | Br | 3 | 80.2 ± 8.8 | 234 ± 0.5 | 2.9 | |
258e | I | 3 | 119 ± 11 | 2200 ± 1250 | 18.5 | |
258f | H | 5 | 99.0 ± 28 | 550 ± 63 | 5.5 | |
259 | 616 ± 88 | 55200 ± 20000 | 89.3 |
class="wikitable sortable"
|+N-substituted 3α[bis(4′-fluorophenyl)methoxy]tropanes ! Compound ! S. Singh's ! R ! Ki (nM) ! IC50 (nM) ! Selectivity | |||||
rowspan=23|200px | |||||
260 (AHN 2-003) | H | 11.2 ± 11 | 9.7 | 0.9 | |
261a | 3-phenylpropyl | 41.9 ± 11 | 230 | 5.5 | |
261b | indole-3-ethyl | 44.6 ± 11 | 1200 | 26.9 | |
261c | 4-phenylbutyl | 8.51 ± 14 | 39 | 4.6 | |
261d | 4-(4′-nitrophenyl)butyl | 20.2 ± 11 | 650 | 32.2 | |
261e | 3-(4′-fluorophenyl)propyl | 60.7 ± 12 | - | - | |
262a | n-butyl | 24.6 ± 8 | 370 | 15.0 | |
262b | cyclopropylmethyl | 32.4 ± 9 | 180 | 5.5 | |
262c | allyl | 29.9 ± 10 | 14 | 0.5 | |
262d | benzyl | 82.2 ± 15 | 290 | 3.5 | |
262e | 4-fluorobenzyl | 95.6 ± 10 | 200 | 2.1 | |
262f | cinnanyl | 86.4 ± 12 | 180 | 2.1 | |
262g | [bis(4-fluorophenyl)methoxy]ethyl | 634 ± 23 | - | - | |
262h | [(4-nitrophenyl)phenylmethoxy]ethyl | 57.0 ± 17 | - | - | |
263 | acetyl | 2340 | 4600 | 2.0 | |
264 | formyl | 2020 ± 13 | 5400 | 2.7 | |
265a | tosyl | 0%ɑ | - | - | |
265b | mesyl | 18%ɑ | - | - | |
(AHN 2-005){{cite journal|last1=Loland|first1=C. J.|last2=Desai|first2=R. I.|last3=Zou|first3=M.-F.|last4=Cao|first4=J.|last5=Grundt|first5=P.|last6=Gerstbrein|first6=K.|last7=Sitte|first7=H. H.|last8=Newman|first8=A. H.|last9=Katz|first9=J. L.|last10=Gether|first10=U.|title=Relationship between Conformational Changes in the Dopamine Transporter and Cocaine-Like Subjective Effects of Uptake Inhibitors|journal=Molecular Pharmacology|volume=73|issue=3|year=2007|pages=813–823|issn=0026-895X|doi=10.1124/mol.107.039800|pmid=17978168|s2cid=5061034}} | CH2CH=CH2 | - | - | - | |
(JHW 007) | CH2CH2CH2CH3 | - | - | - | |
(GA 2-99) | CH2CH2NH2 | - | - | - | |
(GA 103) | CH2CH2CH2CH2Ph | - | - | - | |
200px | 266 | 108 ± 12 | 130 | 1.2 |
ɑInhibition at 10 μM
class="wikitable sortable"
|+8-Oxa-2-carbomethoxy norbenztropines ! Compound ! S. Singh's ! ! IC50 (nM) ! IC50 (nM) | ||||
200px | R/S-268 | 2β,3β | >10000 | >1660 |
R/S-269 | 2α,3β | 20300 | >1660 | |
R/S-270 | 2α,3α | 22300 | >1660 | |
200px | R/S-271 | 2β,3α | 520 | >1660 |
The binding of benztropine analogues to the DAT differs significantly from that of cocaine and the phenyltropanes. Benztropines are considered to be "atypical" DAT ligands because they stabilize the DAT in an inward-facing (closed-to-out) conformation, whereas cocaine and the phenyltropanes stabilize the DAT in an outward-facing (open-to-out) conformation. This difference in DAT binding may be responsible for the lack of cocaine-like behavioral effects observed in animal and human studies of the benztropine analogues and other “atypical” DAT inhibitors. {{cite journal | pmc = 3684841 | pmid=23568856 | doi=10.1124/jpet.111.191056 | volume=346 | issue=1 | title=Nonclassical pharmacology of the dopamine transporter: atypical inhibitors, allosteric modulators, and partial substrates | year=2013 | journal=J. Pharmacol. Exp. Ther. | pages=2–10 | last1 = Schmitt | first1 = KC | last2 = Rothman | first2 = RB | last3 = Reith | first3 = ME}} Studies of the structure-activity relationships of benztropine have shown that DAT affinity and selectivity over other monoamine transporters is enhanced by 4′,4′-difluorination. Modification of the tropane n-substituent was found to mitigate the anticholinergic effects of benztropine analogues by reducing M1 affinity.{{cite journal | last1 = Rothman | first1 = RB | last2 = Baumann | first2 = MH | last3 = Prisinzano | first3 = TE | last4 = Newman | first4 = AH | year = 2008 | title = Dopamine transport inhibitors based on GBR12909 and benztropine as potential medications to treat cocaine addiction | journal = Biochem Pharmacol | volume = 75 | issue = 1| pages = 2–16 | doi = 10.1016/j.bcp.2007.08.007 | pmid = 17897630 | pmc = 2225585 }}{{cite journal | last1 = Runyon | first1 = SP | last2 = Carroll | first2 = FI | year = 2006 | title = Dopamine transporter ligands: recent developments and therapeutic potential | journal = Curr Top Med Chem | volume = 6 | issue = 17| pages = 1825–43 | doi = 10.2174/156802606778249775 | pmid = 17017960 }}
=Tropanyl Isoxazoline Analogues=
role="presentation" class="wikitable mw-collapsible mw-collapsed"
|+ class="nowrap" | Tropanyl-Δ2-isoxazoline derivativesC. Dallanoce et al. - Bioorg. Med. Chem. 20 (2012) 6344-6355 | |||
4a | 4c | 5a | 5c |
---|---|---|---|
x200px | x210px | x190px | x210px |
6a | 6b | 6c | 7a |
x170px | x170px | x170px | x170px |
7b | 7c | 8a | 8b |
x170px | x190px | x190px | x170px |
8c | 9a | 9b | 9c |
x170px | x170px | x170px | x190px |
10a | 10b | 10c | 11a |
x170px | x170px | x190px | x180px |
11b | 12a | 12b | |
x180px | x180px | x180px |
Compound 7a (3′-methoxy-8-methyl-spiro(8-azabicyclo(3.2.1)octane-3,5′(4′H)-isoxazole) allosterically enhances SERT binding of other reuptake ligands. Compound 7a construed as a potentiating allosteric effect (by unveiling occluded configured serotonin uptake-area ligand-site on surface of transporter that allows for binding by exogenous ligand, when SERT is otherwise conformed in a transitional manner where a SERT ligand cannot bind, this effect with compound in question occurs) at concentrations of 10μM—30μM (wherein it acts by interconverting the conformational state of unexposed SERTs to ones exposing the SSRI binding site via a shift to the equilibrium of the MAT) while exerting an inhibitory orthosteric effect when concentrations reach >30μM and above.
7a is the only known compound to allosterically modulate SERT in such a way within in vitro conditions (tianeptine has been shown to do similar, but has only shown efficacy doing so in living in vivo tissue samples). Considering its noncompetitive inhibition of 5-HT transporters decreasing Vmax with small change in the Km for serotonin, putatively stabilizing the cytoplasm-facing conformation of SERT: in such respect it is considered to have the opposite effect profile of the anti-addiction drug ibogaine (save for the function by which its anti-addictive properties are thought to be mediated, i.e. α3β4 nicotinic channel blockage. cf. 18-Methoxycornaridine for such nicotinergic activity without the likewise SERT affinity).{{cite journal|last1=Dallanoce|first1=Clelia|last2=Canovi|first2=Mara|last3=Matera|first3=Carlo|last4=Mennini|first4=Tiziana|last5=De Amici|first5=Marco|last6=Gobbi|first6=Marco|last7=De Micheli|first7=Carlo|title=A novel spirocyclic tropanyl-Δ2-isoxazoline derivative enhances citalopram and paroxetine binding to serotonin transporters as well as serotonin uptake|journal=Bioorganic & Medicinal Chemistry|volume=20|issue=21|year=2012|pages=6344–6355|issn=0968-0896|doi=10.1016/j.bmc.2012.09.004|pmid=23022052}}
Compound 11a possesses similar effects, but acts on the DAT. Similarly, such peripheral DAT considerations (when, as often is, considered conformational rather than otherwise explained as being electrostatic) may constitute the difference in affinity, through allosertic occulsion, between cyclopentyl-ruthenium phenyltropane in its difference from the tricarbonyl-chromium
=Alicyclic Amine Analogues=
class="wikitable" | |
EXP-561 | Butyltolylquinuclidine |
---|---|
x160px | x130px |
=Dihydroimidazoles=
File:Mazindol analogs 2.svg molecular structure.]]
See: List of Mazindol analogues
Mazindol is usually considered a non-habituating (in humans, and some other mammals, but is habituating for e.g. Beagles{{efn| ←[https://www.erowid.org/archive/rhodium/pdf/cocaineanalogs.pdf#87 Page #1,011 (87th page of article)] §VII (7) 1st ¶.}}) tetracyclic dopamine reuptake inhibitor (of somewhat spurious classification in the former).
It is a loosely functional analog used in cocaine research; due in large part to N-Ethylmaleimide being able to inhibit approximately 95% of the specific binding of [3H]Mazindol to the residues of the MAT binding site(s), however said effect of 10 mM N-Ethylmaleimide was prevented in its entirety by just 10 μM cocaine. Whereas neither 300 μM dopamine or D-amphetamine afforded sufficient protection to contrast the efficacy of cocaine.{{efn| ←[https://www.erowid.org/archive/rhodium/pdf/cocaineanalogs.pdf#45 Page #969 (45th page of article)] 2nd (right-side) column 2nd ¶.}}
Local anesthetics (not usually CNS stimulants)
{{multiple image
| direction = vertical
| image1 = Amylocaine.svg
| width1 = 220
| caption1 = Amylocaine, or Stovaine (above), the first synthetically constructed local anesthetic. Compare structure to dimethylaminopivalophenone (below), an analgesic (opioid). Cocaine's classification as a narcotic under U.S. legal code, as has been stretched to be medicinally rationalized such when defining terms very broadly (due to its topical numbing affect, hindering pain signals from CNS recognition via local anesthesia) usually considered an exaggeration of traditional medicine naming convention, in this instance between the first synthetic sodium channel blocker and one of the very simplest opioids there remains a measure of apparent structural similarity between the former anesthetic and latter analgesic "narcotic"; despite the highly differing methods of action for the respective 'pain-killing' properties of either.{{cite journal | last1 = Ruetsch | first1 = YA | last2 = Böni | first2 = T | last3 = Borgeat | first3 = A | date = Aug 2001 | title = From cocaine to ropivacaine: the history of local anesthetic drugs | journal = Curr Top Med Chem | volume = 1 | issue = 3| pages = 175–82 | pmid = 11895133 | doi=10.2174/1568026013395335}}
| image2 = 3-(dimethylamino)-2,2-dimethyl-1-phenylpropan-1-one.svg
| width2 = 220
}}
In animal studies, certain of the local anesthetics have displayed residual dopamine reuptake inhibitor properties,{{cite journal|last1=Wilcox |first1=K.M. |last2=Kimmel |first2=H.L. |last3=Lindsey |first3=K.P. |last4=Votaw |first4=J.R. |last5=Goodman |first5=M.M. |last6=Howell |first6=L.L. |year=2005 |title=In vivo comparison of the reinforcing and dopamine transporter effects of local anesthetics in rhesus monkeys |url=http://research.yerkes.emory.edu/Howell/Synapse58.pdf |journal=Synapse |volume=58 |issue= 4|pages=220–228 |doi=10.1002/syn.20199 |pmid=16206183 |url-status=dead |archive-url=https://web.archive.org/web/20100611201857/http://research.yerkes.emory.edu/Howell/Synapse58.pdf |archive-date=2010-06-11 |citeseerx=10.1.1.327.1264 |s2cid=15631376 }} although not normally ones that are easily available. These are expected to be more cardiotoxic than phenyltropanes. For example, dimethocaine has behavioral stimulant effects (and therefore not here listed below) if a dose of it is taken that is 10 times the amount of cocaine. Dimethocaine is equipotent to cocaine in terms of its anesthetic equivalency. Intralipid "rescue" has been shown to reverse the cardiotoxic effects of sodium channel blockers and presumably those effects when from cocaine administered intravenously as well.
See also
File:Cinnamoylcocaine.svg, an alkaloid widely considered inactive in its own right, but postulated to be active under pyrolysis. (cf. alkylphenyltropane analogue "224e") It is, however, found in patents of active cocaine analogue structures.{{US patent|6479509}} Patent inventor Frank Ivy Carroll, Assignee: Research Triangle Institute[https://patentimages.storage.googleapis.com/US6479509B1/US06479509-20021112-C00016.png U.S. patent US6479509 B1 structures given for submission, 5th compound down in image.]|right|x150px]]
- Coca alkaloids, the ones relating to cocaine biosynthesis include: benzoylecgonine, ecgonidine, ecgonine, hydroxytropacocaine, methylecgonine cinnamate, tropacocaine & truxilline
- Cocaine metabolites (Human), which include: benzoylecgonine (BE), ecgonine methyl ester (EME), ecgonine, norcocaine, p-hydroxycocaine, m-hydroxycocaine, p-hydroxybenzoylecgonine (pOHBE) & m-hydroxybenzoylecgonine
- Dopaminergics
- List of modafinil analogues and derivatives
- Federal Analog Act
- Pharmacophore
- Pharmacopoeia
- Pharmacokinetics
- Pharmacodynamics
Common analogues to prototypical D-RAs:
Notes (inclu. specific locations of citations from within references used)
{{Notelist|20em}}
References
{{Reflist}}
External links
{{commons category|Cocaine analogs}}
- [https://patentscope.wipo.int/search/docs2/pct/WO2003099783/pdf/-802z7YF4iQjMmVVI7bJzC0WHQx658bcq6e_WpnY1uY U. S. Provisional Patent Application listing examples of compounds which are tropanes for prospective use in research]
- [http://www.emory.edu/ACAD_EXCHANGE/2001/octnov/kuharqa.html Article on cocaine analogue research] {{Webarchive|url=https://web.archive.org/web/20060922070754/http://www.emory.edu/ACAD_EXCHANGE/2001/octnov/kuharqa.html |date=2006-09-22 }}
- [http://chemicalland21.com/info/TROPANYL%20COMPOUNDS.htm List of tropanyl type molecules] and their CAS Registry Numbers
{{Phenyltropanes}}
{{Stimulants}}
{{Chemical classes of psychoactive drugs}}
{{DEFAULTSORT:Cocaine Analogues}}