List of cocaine analogues

List of cocaine analogues
Cocaine with it's numerical substitution positions.

This is a list of cocaine analogues. A cocaine analogue retains 3β-benzoyloxy or similar functionality unlike phenyltropanes. Cocaine analogues proper consist of the nine following classes of compounds:[1]

  • 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-subtituted cocaines
  • 6-alkyl-3-benzyl tropanes
  • piperidine homologues of cocaine

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 anesthetics and phenyltropane stimulant dopamine reuptake inhibitor ligands (such as certain piperidines). Many of the stimulant created analogues are of a class of C-2 substituted benzoyloxytropanes.

Contents

Analogs sensu stricto

Cocaine Stereoisomers

There are eight stereoisomers of cocaine.
Stereoisomer IC50 (nM)
R-cocaine 102
edit] Benzoyl- branch cleavage substitutions (excluding the exhaustive phenyl- group) & active transesterification metabolites of cocaine

Miscellaneous stimulant analogues

Alternate two-dimensional molecular diagram of cocaine; shown specifically as a protonated, NH+, hydrochloride, and disregarding 3D stereochemistry

Analogues with both stimulant & local anesthetic effects

See some of Clarke's contributions

Quinuclidine Analogues

  • Butyltolylquinuclidine

Phenyltropanes series (excluding all other benzoyl- branch substitutions)

See: List of phenyltropanes

Piperidine Analogues

Alternate 2D of cocaine's tropane-ring substitution positions.

Organochloride Analogues

GBR Analogs

Benztropine Analogs

  • Benztropine
  • Difluoropine (more selective as a DARI than cocaine. Also an anticholinergic & antihistamine)
  • AHN 1-055 Same structure as for benztropine but 4',4'-bisfluorinated.
  • GA 103 N-phenylpropyl bis-4-fluorobenztropine
  • JHW 007[5] N-(n-butyl)-3α-[bis(4'-fluorophenyl)methoxy]-tropane
A selection of "front bridged" & "back bridged" cocaine analogs.

"Difluoropine" is not a phenyltropane but actually belongs to the benztropine family of DRIs.
In certain respects these are important because they share SAR overlap with GBR 12909 and related analogs.

SARs have shown that 4',4'-difluorination is an excellent way to boost DAT activity of benztropine, and gives excellent selectivity over the SERT and the NET.[6][7]

Furthermore, replacing the N-Me with, e.g. n-phenylpropyl helps to bring muscarinic activity down to something that is the same as DRI affinty.[6]

This is remarkable considering unmodified (native) benztropine is 60 times more active as an anticholinergic than as a dopaminergic.[6]

M1 receptor considerations aside, analogues of this benztropine class still won't substitute for cocaine, and have no propensity to elevate locomotor activity.

Phenethylamines

Many phenethylamines are dopamine releasers, however, certain drugs of the family inhibit dopamine reuptake & transport which may be loosely classed as cocaine analogs. Dependent upon their specific configurations.

Local anesthetics (not usually CNS stimulants)

Note: Certain of the local anesthetics still have residual DRI properties,[8] 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.[8]

Analogues for other purposes

See also

Common analogues to prototypical DRAs:

References

  1. ^ Chemisty, Design, and Structure-Activity Relationship of Cocaine Antagonists. Satendra Singh et al. Chem. Rev. 2000, 100. 925-1024. Final paragraph pg. 45
  2. ^ Gatley SJ, Yu DW, Fowler JS, MacGregor RR, Schlyer DJ, Dewey SL, Wolf AP, Martin T, Shea CE, Volkow ND (March 1994). "Studies with differentially labeled [11C]cocaine, [11C]norcocaine, [11C]benzoylecgonine, and [11C]- and 4'-[18F]fluorococaine to probe the extent to which [11C]cocaine metabolites contribute to PET images of the baboon brain". Journal of Neurochemistry 62 (3): 1154–62. doi:10.1046/j.1471-4159.1994.62031154.x. PMID 8113802. 
  3. ^ Benzoylthio-. cocaine, analogue substitution
  4. ^ Smith, R. Martin; Poquette, Michael A.; Smith, Paula J., "Hydroxymethoxybenzoylmethylecgonines: New metabolites of cocaine from human urine." Journal of Analytical Toxicology 1984, 8(1), pp.29-34
  5. ^ Tanda G, Newman A, Ebbs AL, Tronci V, Green J, Tallarida RJ, Katz JL.Combinations of Cocaine with other Dopamine Uptake Inhibitors: Assessment of Additivity. J Pharmacol Exp Ther. 2009 May 29. PMID 19483071
  6. ^ a b c Rothman RB, Baumann MH, Prisinzano TE, Newman AH. Dopamine transport inhibitors based on GBR12909 and benztropine as potential medications to treat cocaine addiction. Biochem Pharmacol. 2008 Jan 1;75(1):2-16. doi:10.1016/j.bcp.2007.08.007 PMID 17897630
  7. ^ Runyon SP, Carroll FI. Dopamine transporter ligands: recent developments and therapeutic potential. Curr Top Med Chem. 2006;6(17):1825-43. doi:10.2174/156802606778249775 PMID 17017960
  8. ^ a b Wilcox, K.M., Kimmel, H.L., Lindsey, K.P., Votaw, J.R., Goodman, M.M., Howell, L.L. In vivo comparison of the reinforcing and dopamine transporter effects of local anesthetics in rhesus monkeys. Synapse, 58: 220-228, 2005. PDF

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