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: 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.

Analogs sensu stricto

Cocaine Stereoisomers

Structure Stereoisomer IC50 (nM)[3H]WIN 3542 inhibition to rat striatal membranesMean error standard ≤5% in all cases IUPACnomenclatureR-cocaine(Erythroxyline) 102 methyl(1R,2R,3S,5S)-3-(benzoyloxy)-8-methyl-8-azabicyclo[3.2.1]octane-2-carboxylate R-pseudococaine(Delcaine, Depsococaine, Dextrocaine, Isococaine, Psicaine.) 172 15800 methyl(1R,2S,3S,5S)-3-(benzoyloxy)-8-methyl-8-azabicyclo[3.2.1]octane-2-carboxylate R-allococaine 173 6160 methyl(1R,2R,3R,5S)-3-(benzoyloxy)-8-methyl-8-azabicyclo[3.2.1]octane-2-carboxylate R-allopseudococaine 174 28500 methyl(1R,2S,3R,5S)-3-(benzoyloxy)-8-methyl-8-azabicyclo[3.2.1]octane-2-carboxylate S-cocaine 175 15800 methyl(1S,3R,4R,5R)-3-(benzoyl)oxy-8-methyl-8-azabicyclo[3.2.1]octane-4-carboxylate S-pseudococaine 176 22500 methyl(1S,3R,4S,5R)-3-(benzoyl)oxy-8-methyl-8-azabicyclo[3.2.1]octane-4-carboxylate S-allococaine 177 9820 methyl(1S,3S,4R,5R)-3-(benzoyl)oxy-8-methyl-8-azabicyclo[3.2.1]octane-4-carboxylate S-allopseudococaine 178 67700 methyl(1S,3S,4S,5R)-3-(benzoyl)oxy-8-methyl-8-azabicyclo[3.2.1]octane-4-carboxylate

There are eight stereoisomers of cocaine (excluding mesomers and modifications to the internal portion of the tropane ring). 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.

Arene benzene-ring 2′, 3′, 4′ (5′ & 6′) position (aryl) substitutions

para-substituted benzoylmethylecgonines +Carbon 4′-hydrogen Substitutions (benzene-4′ "para" substituted benzoyloxytropanes)Data-set congruent to, and aggregate with, following tablesIC50 values Structure S. Singh'salphanumericassignation(name) 4′=R DAT [3H]WIN 35428 5-HTT [3H]Paroxetine NET [3H]Nisoxetine Selectivity 5-HTT/DAT Selectivity NET/DAT CocaineH249 ± 37615 ± 1202500 ± 702.510.0non-benzoyloxy analoguecomparative ligands11b (WIN 35428)(nisoxetine)(fluoxetine)F——24 ± 4775 ± 205200 ± 1270690 ± 14762 ± 9015 ± 3258 ± 40135 ± 21963 ± 15828.71.00.00310.70.20.2 183a I 2522 ± 41052 ± 2318458 ± 10730.47.3 183b Ph 486 ± 63 - - - - 183c OAc 144 ± 2 - - - - 183d OH 158 ± 83104 ± 148601 ± 1119.63.8 (4′-Fluorococaine) F - - - - - (para-Isothiocyanatobenzoylecgoninemethyl ester)(p-Isococ) NCS - - - - - para-substituted benzoylmethylecgonines 183a 183b 183c 183d 4'-Fluorococaine P-ISOCOC 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.

meta-substituted benzoylmethylecgonines +Carbon 3′-hydrogen Substitutions (benzene-3′ "meta" substituted benzoyloxytropanes)Data-set congruent to, and aggregate with, preceding and following tablesIC50 values Structure S. Singh'salphanumericassignation(name) 3′=R DAT [3H]WIN 35428 5-HTT [3H]Paroxetine NET [3H]Nisoxetine Selectivity 5-HTT/DAT Selectivity NET/DAT (cocaine)H249 ± 37615 ± 1202500 ± 702.510.0 184a I 325ɑ - - - - 184b OH 1183 ± 115793 ± 333760 ± 5890.73.2 191 OBn - - - - - (m-Isococ) NCS - - - - - ɑIC50 value for displacement of [3H]cocaine meta-substituted benzoylmethylecgonines 184a 184b m-ISOCOC C3-Benzyloxycocaine

ortho-substituted benzoylmethylecgonines +Carbon 2′-hydrogen Substitutions (benzene-2′ "ortho" substituted benzoyloxytropanes)Data-set congruent to, and aggregate with, preceding and following tablesIC50 values Structure S. Singh'salphanumericassignation(name) 2′=R DAT [3H]WIN 35428 5-HTT [3H]Paroxetine NET [3H]Nisoxetine Selectivity 5-HTT/DAT Selectivity NET/DAT CocaineH249 ± 37615 ± 1202500 ± 702.510.0 185a I 350ɑ - - - - 185b F 604 ± 671770 ± 3091392 ± 1732.92.3 185c(2′-Acetoxycocaine) OAc 70 ± 1219 ± 2072 ± 93.11.0 185d(2′-Hydroxycocaine)et. et. OH 25 ± 4143 ± 2148 ± 25.71.9 ɑIC50 value for displacement of [3H]cocaine ortho-substituted benzoylmethylecgonines 185a 185b 185c 185d The hydroxylated 2′-OH analogue exhibited a tenfold increase in potency over cocaine.

Manifold and termination benzoyloxy phenyl-substitutions

Vanillylmethylecgonine 186b

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.

+Manifold Compositions of Terminating Phenyl Ring Substitutions (Multiple benzene-2′,3′ & 4′ combined substituted benzoyloxytropanes)Data-set (excepting instanced references inside table) congruent to, and aggregate with, preceding and following tablesIC50 values Structure S. Singh'salphanumericassignation(name) 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 186 HO H I 215 ± 19195 ± 101021 ± 750.94.7 (Vanillylmethylecgonine) H OCH3 OH - - - - -

+Terminating Phenyl Carbon Ring Fusions & AlterationsData-set congruent to, and aggregate with, preceding tableIC50 values Structure S. Singh'salphanumericassignation(name) C=R DAT [3H]Cocaine (IC50) 187 1-naphthalene 742 ± 48 188 2-naphthalene 327 ± 63

Benzoyl and carbomethoxy branch modifications

Benzoylthiomethylecgonine

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)

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

+C1 substitutionsKi values for uptake inhibition obtained on HEK-293 heterologously expressed human monoamine transporter cells. Full article Structure Trivial name Ki (nM) @ DAT Ki (nM) @ SERT Ki (nM) @ NET σ1 affinityKi σ2 affinityKi IC50 (μM) Na+ inhibition(Vertridine-Stimulatedinflux of sodium channelsin Neocortical neurons)c (—)-Cocaine H 326 ± 106513 ± 143358 ± 696.7 ± 0.3 μMd"significant"6.99 ± 2.432.30 (—)-1-methyl-cocaine Me 163 ± 23435 ± 77488 ± 101"unappreciable"1.13 μM16.01 ± 1.902.67 (—)-1-ethyl-cocaine Et 95.1 ± 17.0ɑ1,106 ± 112598 ± 179———3.20 (—)-1-n-propyl-cocainen-Pr 871 ± 205ɑ2,949 ± 462b796 ± 195———3.56 (—)-1-n-pentyl-cocainen-C5H11 1,272 ± 199b1,866 ± 400ɑ1,596 ± 21b———4.64 (—)-1-phenyl-cocaine Ph 32.3 ± 5.7b974 ± 3081,980 ± 99b524 nM198 nM0.29 ± 0.073.77 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.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.

2β-substitutions

+Direct 2β Substitutions(IC50 nM values) Structure S. Singh'salphanumericassignation(name) R DAT [3H]WIN 35428 5-HTT [3H]Paroxetine NET [3H]Nisoxetine Selectivity 5-HTT/DAT Selectivity