List of phenyltropanes#η6-3β-(transition metal complexed phenyl)tropanes

File:Epibati-tropane.svg|Epibatropane{{US patent|6479509}} containing a nitrogen heteroatom in the benzene ring formation.

File:Tamagnan.png|Tamagnan:{{cite journal | doi = 10.1016/j.bmcl.2004.12.014 | title=Synthesis and monoamine transporter affinity of new 2β-carbomethoxy-3β-[4-(substituted thiophenyl)]phenyltropanes: discovery of a selective SERT antagonist with picomolar potency | journal=Bioorganic & Medicinal Chemistry| date=2005 | volume=15 | issue=4 | pages=1131–1133 | first=Gilles | last=Tamagnan | pmid=15686927}} SSRI, SERT = 17(pM) = 10 times the strength of paroxetine for 5HT.

File:RTI-298.svg|RTI-298

File:RTI-11W.svg|(4′-)para-cis-propenyl-phenyl-methylecgonine. A rare SDRI compound with negligible NET affinity (>2,800.0nM displacement value for NET ligand) that retains significant DAT & SERT (15.0nM & 7.1nM) affinity.

File:Carroll 15.svg|C2-C3 unsaturated (non-isomeric, neither α nor β orientated) 2-naphthyl-tropane

File:Carroll 13.svg|1-naphthyl-tropane in its usual (comparably non-standard) boat formation of its tropane ring.

Like cocaine, phenyltropanes are considered a 'typical' or 'classical' (i.e. "cocaine-like") DAT re-uptake pump ligands in that they stabilize an "open-to-out" conformation on the dopamine transporter; despite the extreme similarity to phenyltropanes, benztropine and others are in suchwise not considered "cocaine-like" and are instead considered atypical inhibitors insofar as they stabilize what is considered a more inward-facing (closed-to-out) conformational state.{{cite journal | date = Jul 2013 | title = Nonclassical Pharmacology of the Dopamine Transporter: Atypical Inhibitors, Allosteric Modulators, and Partial Substrates| journal = J Pharmacol Exp Ther | volume = 346 | issue = 1| pages = 2–10 Fig. 1 | doi = 10.1124/jpet.111.191056 | pmc=3684841 | pmid=23568856 | last1 = Schmitt| first1 = K. C.| last2 = Rothman| first2 = R. B.| last3 = Reith| first3 = M. E.}}

Considering the differences between PTs and cocaine: 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}} The manner in which this sets phenyltropanes into the binding pocket at MAT is postulated as one possible explanation to account for PTs increased behavioral stimulation profile over cocaine.{{efn|{{Cite journal|url=https://www.erowid.org/archive/rhodium/pdf/cocaineanalogs.pdf|doi=10.1002/chin.200020238|title=Chem Inform Abstract: Chemistry, Design, and Structure-Activity Relationship of Cocaine Antagonists|journal=ChemInform|volume=31|issue=20|pages=no|year=2000|last1=Singh|first1=Satendra}} [https://www.scribd.com/doc/77191354/Satendra-Singh-Chemistry-Design-and-Structure-Activity-Relationship-of-Cocaine-Antagonists Mirror hotlink.] ←[https://www.erowid.org/archive/rhodium/pdf/cocaineanalogs.pdf#47 Page #971 (47th page of article)] 1st ¶, 10th line}}

Blank spacings within tables for omitted data use "no data", "?", "-" or "—" interchangeably.

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File:RTI-318 structure.png

File:RTIthreefivethree.png

File:Phenyltropane 17c.svg

File:RTI-112.svg

• ^ɑas ·HCl (salt)
• ^bas ·HCl·2 H₂O (salt)
• ^cSingh gives the reverse value with respect to i.e. 1,329 for NET & 320 for 5-HT

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• ^ɑIC₅₀ determined in Cynomolgous monkey caudate-putamen
• ^bas ·HCl (salt)
• ^cas ·HCl·2 H₂O (salt)
• ^dNE_N

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^ɑN=2

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^ɑN=2

• ^ɑKi value for displacement of [³H]DA uptake.
• ^bKi value for displacement of [³H]5-HT uptake.
• ^cKi value for displacement of [³H]NE uptake.
• ^d[³H]5-HT uptake to [³H]DA uptake ratio.
• ^e[³H]NE uptake to [³H]DA uptake ratio.

File:RTI-204 structure.png

File:RTIoneonethree.png

File:RTI-120 structure.png

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File:RTI-77 structure.png

File:RTI-121.png

File:RTI-150.png

Use of a cyclopropyl ester appears to enable better MAT retention than does the choice of isopropyl ester.

Use of a ^cycBu resulted in greater DAT selectivity than did the ^cycPr homologue.

{{See also|{{PAGENAME}}#Paroxetine homologues|l1=N-desmethyl Paroxetine homologues|selfref=y}}

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{{US Patent|5736123}}

File:RTI-183 structure.png

File:RTI-229 structure.png

File:RTI-227 structure.png

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✲RTI-183 and RTI-218 suggest possible copy-error, seeing as "CON(OMe)Me" & "CON(Me)OMe" difference between methyl & methoxy render as the same.

File:Phenyltropane para chloro dimer.svg

File:Phenyltropane para methyl dimer.svg

File:PhenyltropaneDimerC2Benzenelink.svg

File:PhenyltropaneDimerC2amide.svg

File:PhenyltropaneDimer.svg

Dimers of phenyltropanes, connected in their dual form using the C2 locant as altered toward a carboxamide structural configuring (in contrast and away from the usual inherent ecgonine carbmethoxy), as per Frank Ivy Carroll's patent inclusive of such chemical compounds, possibly so patented due to being actively delayed pro-drugs in vivo.

These heterocycles are sometimes referred to as the "bioisosteric equivalent" of the simpler esters from which they are derived. A potential disadvantage of leaving the ββ-ester unreacted is that in addition to being hydrolyzable, it can also epimerize{{Cite journal

| pmid = 8411004

| year = 1993

| last1 = Carroll | first1 = F. I.

| last2 = Gray

| last3 = Abraham

| last4 = Kuzemko

| last5 = Lewin

| last6 = Boja

| last7 = Kuhar

| title = 3-Aryl-2-(3′-substituted-1′,2′,4'-oxadiazol-5′-yl)tropane analogues of cocaine: affinities at the cocaine binding site at the dopamine, serotonin, and norepinephrine transporters

| volume = 36

| issue = 20

| pages = 2886–2890

| journal = Journal of Medicinal Chemistry

| doi = 10.1021/jm00072a007

}} to the energetically more favorable trans configuration. This can happen to cocaine also.

File:HeterocyclicMEPCmpndModel34.png

Several of the oxadiazoles contain the same number and types of heteroatoms, while their respective binding potencies display 8×-15× difference. A finding that would not be accounted for by their affinity originating from hydrogen bonding.

To explore the possibility of electrostatic interactions, the use of molecular electrostatic potentials (MEP) were employed with model compound 34 (replacing the phenyltropane moiety with a methyl group). Focusing on the vicinity of the atoms @ positions A—C, the minima of electrostatic potential near atom position A (ΔV_min(A)), calculated with semi-empirical (AM1) quantum mechanics computations (superimposing the heterocyclic and phenyl rings to ascertain the least in the way of steric and conformational discrepancies) found a correlation between affinity @ DAT and ΔV_min(A): wherein the values for the latter for 32c = 0, 32g = -4, 32h = -50 & 32i = -63 kcal/mol.

In contrast to this trend, it is understood that an increasingly negative ΔV_min is correlated with an increase of strength in hydrogen bonding, which is the opposing trend for the above; this indicates that the 2β-substituents (at least for the heterocyclic class) are dominated by electrostatic factors for binding in-the-stead of the presumptive hydrogen bonding model for this substituent of the cocaine-like binding ligand.{{efn| ←[https://www.erowid.org/archive/rhodium/pdf/cocaineanalogs.pdf#16 Page #940 (16th page of article)] underneath Table 8., above § 4}}

File:3-R-isoxazol-5-yl.svg

File:RTI-130 structure.png

File:RTI-126.png

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| perrow = 2

| image1 = RTI-470 structure.png

| width1 = 220

| caption1 = RTI-4229-470 structure. Highly excited 94 pM DAT signal.{{Cite journal

| last1 = Carroll | first1 = F.

| last2 = Howard | first2 = J.

| last3 = Howell | first3 = L.

| last4 = Fox | first4 = B.

| last5 = Kuhar | first5 = M.

| title = Development of the dopamine transporter selective RTI-336 as a pharmacotherapy for cocaine abuse

| journal = The AAPS Journal

| volume = 8

| issue = 1

| pages = E196–E203

| year = 2006

| pmid = 16584128

| doi = 10.1208/aapsj080124

| pmc = 2751440

}}

↑ above: 2D skeletal depiction.

↓ below: 3D tube model.

| image3 = RTI-4229-470 with tube model.png

| width3 = 220

| image4 = Heterocyclic tropanes.png

| width4 = 220

| image2 = RTI-371 structure.png

| width2 = 220

}}

File:Heterocyclic phenyltropane syntheses p2.png, Kuhar, et al. {{US patent|5,935,953}} (1999).]]

N.B There are some alternative ways of making the tetrazole ring however; Cf. the sartan drugs synthesis schemes. Bu₃SnN₃ is a milder choice of reagent than hydrogen azide (cf. Irbesartan).

File:WF-23.svg|

File:WF-31.svg|

File:WF-11.svg|

File:WF-33.svg|

File:3ß-(5-Indolyl)-8-azabicyclo(3.2.1)octanes.png|Indolyl{{cite journal|last1=Davies|first1=Huw M.L|last2=Ren|first2=Pingda|last3=Kong|first3=Norman|last4=Sexton|first4=Tammy|last5=Childers|first5=Steven R|title=Synthesis and monoamine transporter affinity of 3β-(4-(2-pyrrolyl)phenyl)-8-azabicyclo[3.2.1]octanes and 3β-(5-Indolyl)-8-azabicyclo[3.2.1]octanes|journal=Bioorganic & Medicinal Chemistry Letters|volume=11|issue=4|year=2001|pages=487–489|issn=0960-894X|doi=10.1016/S0960-894X(00)00701-0|pmid=11229754}}
cf. the Tamagnan series of phenyltropanes for examples with a methylene unit spacer breaking up the indole.

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Note: p-fluorophenyl is weaker than the others. RTI-145 is not peroxy, it is a methyl carbonate.

File:RTI-123 structure.png

^aK_i value for displacement of WIN 35428.

^bIC₅₀ value.

{{multiple image

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| header = Compound 48

| image1 = Compound 48-H.svg

| width1 = 220

| caption1 = para-hydro

| image2 = Compound 48-Cl.svg

| width2 = 260

| caption2 = para-chloro

}}

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Irreversible (phenylisothiocyanate) binding ligand ({{Cite journal

| last1 = Murthy | first1 = V.

| last2 = Martin | first2 = T. J.

| last3 = Kim | first3 = S.

| last4 = Davies | first4 = H. M. L.

| last5 = Childers | first5 = S. R.

| title = In Vivo Characterization of a Novel Phenylisothiocyanate Tropane Analog at Monoamine Transporters in Rat Brain

| doi = 10.1124/jpet.108.138842

| journal = Journal of Pharmacology and Experimental Therapeutics

| volume = 326

| issue = 2

| pages = 587–595

| year = 2008

| pmid = 18492949

| s2cid = 5996473

}}){{Cite journal

| pmid = 1588560

| year = 1992

| last1 = Carroll | first1 = F. I.

| last2 = Gao

| last3 = Abraham

| last4 = Lewin

| last5 = Lew

| last6 = Patel

| last7 = Boja

| last8 = Kuhar

| title = Probes for the cocaine receptor. Potentially irreversible ligands for the dopamine transporter

| volume = 35

| issue = 10

| pages = 1813–1817

| journal = Journal of Medicinal Chemistry

| doi = 10.1021/jm00088a017

}} RTI-76:{{Cite journal

| author1 = Wu| first2 = M.| first3 = Q.| first4 = C.| first5 = F.| first6 = P.

| title = Concurrent autoreceptor-mediated control of dopamine release and uptake during neurotransmission: an in vivo voltammetric study

| journal = Journal of Neuroscience

| volume = 22

| issue = 14

| pages = 6272–6281

| year = 2002

| pmid = 12122086

| pmc = 6757948| last2 = Reith

| last3 = Walker

| last4 = Kuhn

| last5 = Carroll

| last6 = Garris

| doi = 10.1523/JNEUROSCI.22-14-06272.2002}} 4′-isothiocyanatophenyl (1R,2S,3S,5S)-3-(4-chlorophenyl)-8-methyl-8-azabicyclo[3.2.1]octane-2-carboxylate. Also known as: 3β-(p-chlorophenyl)tropan-2β-carboxylic acid p-isothiocyanatophenylmethyl ester.

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HD-205 (Murthy et al., 2007){{cite journal | doi = 10.1124/jpet.108.138842 | pmid=18492949 | volume=326 | title=In vivo characterization of a novel phenylisothiocyanate tropane analog at monoamine transporters in rat brain | date=August 2008 | journal=J. Pharmacol. Exp. Ther. | pages=587–95 | last1 = Murthy | first1 = V | last2 = Martin | first2 = TJ | last3 = Kim | first3 = S | last4 = Davies | first4 = HM | last5 = Childers | first5 = SR| issue=2 | s2cid=5996473 }}

Note the contrast to the phenylisothiocyanate covalent binding site locations as compared to the one on p-Isococ, a non-phenyltropane cocaine analogue.

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One patent claims a series of compounds with biotin-related sidechains are pesticides.

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File:Phenyltropane FMOC-hydrazide.svg

File:Phenyltropane pyrene.svg

File:Phenyltropane dimethylaminonaphthalene.svg

File:Phenyltropane pyrene hydroxamide.svg

{{Cite patent |country= WO |number= 2004113297|title=Aza-ring derivatives and their use as monoamine neurotransmitter re-uptake inhibitors|pubdate=2004-12-29|assign=NeuroSearch AS|inventor1-last=Peters|inventor1-first=Dan |inventor2-last= Olsen|inventor2-first=Gunnar M.|inventor3-last=Nielsen|inventor3-first=Elsebet Oestergaard |inventor4-last=Scheel-Krueger|inventor4-first=Joergen}}

File:WO9713770.svg

{{US patent|2001047028}}

File:RTI-319 structure.png

File:RTI-274 Structure.png

{{center|^ɑ{{US Patent|6358492}}^b{{US Patent|7011813}}^c{{US Patent|7011813}}^d{{US Patent|7291737}}}}

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{{Cite patent|country=CA|number=2112084}}

File:Brasofensine.svg

File:Tesofensine chemical structure.png

File:NStwothreefivenine.png

{{US patent|2001047028}}

{{Cite patent|country=WO|number=2004072075|title=Novel 8-aza-bicyclo[3.2.1]octane derivatives and their use as monoamine neurotransmitter re-uptake inhibitors

|pubdate=2004-08-26|assign=NeuroSearch AS|inventor1-last=Peters|inventor1-first=Dan |inventor3-last= Olsen|inventor3-first=Gunnar M.|inventor2-last=Nielsen|inventor2-first=Elsebet Oestergaard |inventor4-last=Scheel-Krueger|inventor4-first=Joergen}}

File:Cocaine analog 21ab alternate.pngs and perrhenate by a double ligand transfer (DLT) reaction.{{cite journal | pmid = 11792176 | volume=13 | issue=1 | title=Synthesis of cyclopentadienyltricarbonyl rhenium phenyltropanes by double ligand transfer: organometallic ligands for the dopamine transporter | journal=Bioconjug Chem | pages=29–39 | last1 = Cesati | first1 = RR 3rd | last2 = Tamagnan | first2 = G | last3 = Baldwin | first3 = RM | last4 = Zoghbi | first4 = SS | last5 = Innis | first5 = RB | last6 = Kula | first6 = NS | last7 = Baldessarini | first7 = RJ | last8 = Katzenellenbogen | first8 = JA | doi=10.1021/bc010011x | year=2002}}]]

Unlike metal complexed PTs created with the intention of making useful radioligands, 21a & 21b were produced seeing as their η⁶-coordinated moiety dramatically altered the electronic character and reactivity of the benzene ring, as well as such a change adding asymmetrical molecular volume to the otherwise planar arene ring unit of the molecule. (cf. the Dewar–Chatt–Duncanson model). In addition the planar dimension of the transition metal stacked arene becomes delocalized (cf. Bloom and Wheeler.{{cite journal | journal = Angew. Chem. | year = 2011 | volume = 123 | pages = 7993–7995 | doi = 10.1002/ange.201102982 | title = Taking the Aromaticity out of Aromatic Interactions | last1 = Bloom | first1 = Jacob W. G. | last2 = Wheeler | first2 = Steven E. | issue = 34| bibcode = 2011AngCh.123.7993B }}).

21a was twice as potent as both cocaine and troparil in displacement of β-CFT, as well as displaying high & low affinity K_i values in the same manner as those two compounds. Whereas its inhibition of DA uptake showed it as comparably equipotent to cocaine & troparil. 21b by contrast had a one hundredfold decrease in high-affinity site binding compared to cocaine and a potency 10× less for inhibiting DA uptake. Attesting these as true examples relating useful effective applications for bioorganometallic chemistry.

File:Cocaine analog 21a alternate.png containing phenyltropane, having roughly twice the strength K_i affinity as parent compound at same mean affect.]]

The discrepancy in binding for the two benzene metal chelates is assumed to be due to electrostatic differences rather than their respective size difference. The solid cone angles, measured by the steric parameter (i.e. θ) is θ=131° for Cr(CO)₃ whereas Cp*Ru was θ=187° or only 30% larger. The tricarbonyl moiety being considered equivalent to the cyclopenta dienyl (Cp) ligand.

File:Cocaine analog 21b alternate.png

• ^ɑThe binding data fit a two-site model better than a one-site model
• ^bThe K_i value for the one-site model was 124 ± 10 nM
• ^cIUPAC: [η⁶-(2β-carbomethoxy-3β-phenyl)tropane]tricarbonylchromium
• ^dIUPAC: [η⁵-(pentamethylcyclopentadienyl)]-[η⁶-(2β-carbomethoxy-3β-phenyl)tropane]ruthenium-(II) triflate

File:Cocaine analogs - thiophenes and furans.svg

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File:Hanna et al.png|Fluoxetine homologue,[http://www.pubfacts.com/detail/23022052/A-novel-spirocyclic-tropanyl-%CE%94%C2%B2-isoxazoline-derivative-enhances-citalopram-and-paroxetine-binding- A novel spirocyclic tropanyl-Δ²-isoxazoline derivative enhances citalopram and paroxetine binding to serotonin transporters as well as serotonin uptake.] Bioorg Med Chem 2012 Nov 10;20(21):6344-55. Epub 2012 Sep 10. also: Hanna et al. (2007){{cite journal | doi = 10.1016/j.bmc.2007.08.055 | pmid=17870537 | title=Synthesis of some tropane derivatives of anticipated activity on the reuptake of norepinephrine and/or serotonin | journal=Bioorganic | date=2007 | volume=15 | issue=24 | pages=7765–7772 | first=Mona M. | last=Hanna}}
cf. the paroxetine homologue PTs

File:ZIENT.png|ZIENT:{{cite journal | doi = 10.1021/jm0100180 | pmid= 12620070 | title= Synthesis and Characterization of Iodine-123 Labeled 2β-Carbomethoxy-3β-(4′-((Z)-2-iodoethenyl)phenyl)nortropane. A Ligand for in Vivo Imaging of Serotonin Transporters by Single-Photon-Emission Tomography | journal=Journal of Medicinal Chemistry | date=2003 | volume=46 | issue=6 | pages=925–935 | first=Mark M. | last=Goodman}}

• ^ɑIC₅₀ value for displacement of [H³]mazindol. IC₅₀ for cocaine 288 nM for displacement of [H³]mazindol