salicylmethylecgonine

{{Short description|Chemical compound}}

{{Use dmy dates|date=April 2020}}

{{Drugbox

| verifiedrevid = 451551747

| IUPAC_name = methyl (1R,2R,3S,5S)-3-(2-hydroxybenzoyloxy)-8-methyl-8-azabicyclo[3.2.1] octane-2-carboxylate

| image = Salicylecgonine.png

| image_class = skin-invert-image

| width = 220

| tradename =

| CAS_number_Ref = {{cascite|correct|CAS}}

| legal_US = Schedule II

| CAS_number = 89339-17-3

| UNII_Ref = {{fdacite|correct|FDA}}

| UNII = K8J4W658QK

| PubChem = 10519659

| ChemSpiderID = 8695057

| DrugBank_Ref = {{drugbankcite|correct|drugbank}}

| C = 17

| H = 21

| N = 1

| O = 5

| smiles = CN1[C@H]2CC[C@@H]1[C@H]([C@H](C2)OC(=O)C3=CC=CC=C3O)C(=O)OC

| StdInChI = 1S/C17H21NO5/c1-18-10-7-8-12(18)15(17(21)22-2)14(9-10)23-16(20)11-5-3-4-6-13(11)19/h3-6,10,12,14-15,19H,7-9H2,1-2H3/t10-,12+,14-,15+/m0/s1

| StdInChIKey = PEISRHQJLATJPJ-MMMKDXCPSA-N

}}

Salicylmethylecgonine, (2′-Hydroxycocaine) is a tropane derivative drug which is both a synthetic analogue and a possible active metabolite of cocaine.{{cite journal | vauthors = Singh S, Basmadjian GP, Avor K, Pouw B, Seale TW | url = https://www.scribd.com/doc/39496623/salicylmethylecgonine | title = A convenient synthesis of 2'- or 4'-hydroxycocaine | journal = Synthetic Communications | date = 1997 | volume = 27 | issue = 22 | pages = 4003–4012 | doi = 10.1080/00397919708005923 }} Its potency in vitro is around 10x that of cocaine,{{cite journal | vauthors = el-Moselhy TF, Avor KS, Basmadjian GP | title = 2'-substituted analogs of cocaine: synthesis and dopamine transporter binding potencies | journal = Archiv der Pharmazie | volume = 334 | issue = 8–9 | pages = 275–278 | date = September 2001 | pmid = 11688137 | doi = 10.1002/1521-4184(200109)334:8/9<275::aid-ardp275>3.0.co;2-b | s2cid = 41556606 }} although it is only around three times more potent than cocaine when administered to mice (likely owing to it having a higher LogP: 2.89 than that of cocaine: 2.62){{cite journal | vauthors = Seale TW, Avor K, Singh S, Hall N, Chan HM, Basmadjian GP | title = 2'-Substitution of cocaine selectively enhances dopamine and norepinephrine transporter binding | journal = NeuroReport | volume = 8 | issue = 16 | pages = 3571–3575 | date = November 1997 | pmid = 9427328 | doi = 10.1097/00001756-199711100-00030 | s2cid = 24348794 }} Note however that the compound 2′-Acetoxycocaine would act as a prodrug to Salicylmethylecgonine in humans, and has a more efficient partition coefficient which would act as a delivery system and would circumvent this reason for a drop in potency. Salicylmethylecgonine also shows increased behavioral stimulation compared to cocaine similar to the phenyltropanes.{{cite journal | vauthors = Singh S | title = Chemistry, design, and structure-activity relationship of cocaine antagonists | journal = Chemical Reviews | volume = 100 | issue = 3 | pages = 925–1024 | date = March 2000 | pmid = 11749256 | doi = 10.1021/cr9700538 }} The hydroxy branch renders the molecule a QSAR of a 10-fold increase over cocaine in its binding potency for the dopamine transporter & a 52-fold enhanced affinity for the norepinephrine transporter. It also has a reduced selectivity for the serotonin transporter though only due to its greater increase at NET binding; its SERT affinity being 4-fold increased compared to cocaine. However, in overall binding affinity (not uptake inhibition) it displaces ligands better across the board than cocaine in all monoamine categories.

class="wikitable sortable" |+Binding comparison between cocaine and semi-synthetic derivative o-hydroxy-cocaine ! Compound ! DAT [3H]WIN 35428 ! 5-HTT [3H]Paroxetine ! NET [3H]Nisoxetine ! Selectivity 5-HTT/DAT ! Selectivity NET/DAT
Cocaine	249 ± 37	615 ± 120	2500 ± 70	2.5	10.0
2′(ortho)-hydroxycocaine	25 ± 4	143 ± 21	48 ± 2	5.7	1.9

Study of molecular modeling inferred that, in addition to intramolecular hydrogen bonding between the adjacent 3β-carbonyl and the 2′-OH ortho group of 185d (i.e. salicylmethylecgonine), that intermolecular hydrogen bonding between its hydroxy ortho substituent and the dopamine transporter was also possible; and was rationalized to be due to its nearness of where the nitrogen and oxygen atoms reside in the para-hydroxy of dopamine itself and its own intrinsic relation to DAT whereby that mutual hydroxyl functionality is mediated in both salicylmethylecgonine and dopamine in a similar manner. That is, at serine residue 359 on DAT, as the distance of the hydroxy to the bridge-nitrogen on salicylmethylecgonine is 7.96 Å (close to that of the distance between the p-OH & the NH₂ atoms of dopamine, their distance apart being 7.83 Å). Which may play a role in this analogs increased behavioral stimulation over its parent compound cocaine. The meta-hydroxy group of dopamine, by contrast, has a distance of 6.38 Å from its nitrogen and is believed to engage with the 356 residue on DAT.