Novel C-1 substituted cocaine analogs unlike cocaine or benztropine

Maarten E A Reith, Solav Ali, Audrey Hashim, Imran S. Sheikh, Naresh Theddu, Narendra V. Gaddiraju, Suneet Mehrotra, Kyle C. Schmitt, Thomas F. Murray, Henry Sershen, Ellen M. Unterwald, Franklin A. Davis

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Abstract

Despite a wealth of information on cocaine-like compounds, there is no information on cocaine analogs with substitutions at C-1. Here, we report on (R)-(-)-cocaine analogs with various C-1 substituents: methyl (2), ethyl (3), n-propyl (4), n-pentyl (5), and phenyl (6). Analog 2 was equipotent to cocaine as an inhibitor of the dopamine transporter (DAT), whereas 3 and 6 were 3- and 10-fold more potent, respectively. None of the analogs, however, stimulated mouse locomotor activity, in contrast to cocaine. Pharmacokinetic assays showed compound 2 occupied mouse brain rapidly, as cocaine itself; moreover, 2 and 6 were behaviorally active in mice in the forced-swim test model of depression and the conditioned place preference test. Analog 2 was a weaker inhibitor of voltage-dependent Na+ channels than cocaine, although 6 was more potent than cocaine, highlighting the need to assay future C-1 analogs for this activity. Receptorome screening indicated few significant binding targets other than the monoamine transporters. Benztropine-like "atypical" DAT inhibitors are known to display reduced cocaine-like locomotor stimulation, presumably by their propensity to interact with an inward-facing transporter conformation. However, 2 and 6, like cocaine, but unlike benztropine, exhibited preferential interaction with an outward-facing conformation upon docking in our DAT homology model. In summary, C-1 cocaine analogs are not cocaine-like in that they are not stimulatory in vivo. However, they are not benztropine-like in binding mechanism and seem to interact with the DAT similarly to cocaine. The present data warrant further consideration of these novel cocaine analogs for antidepressant or cocaine substitution potential.

Original languageEnglish
Pages (from-to)413-425
Number of pages13
JournalJournal of Pharmacology and Experimental Therapeutics
Volume343
Issue number2
DOIs
StatePublished - Nov 2012

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Benztropine
Cocaine
Dopamine Plasma Membrane Transport Proteins

All Science Journal Classification (ASJC) codes

  • Pharmacology
  • Molecular Medicine

Cite this

Reith, M. E. A., Ali, S., Hashim, A., Sheikh, I. S., Theddu, N., Gaddiraju, N. V., ... Davis, F. A. (2012). Novel C-1 substituted cocaine analogs unlike cocaine or benztropine. Journal of Pharmacology and Experimental Therapeutics, 343(2), 413-425. https://doi.org/10.1124/jpet.112.193771

Novel C-1 substituted cocaine analogs unlike cocaine or benztropine. / Reith, Maarten E A; Ali, Solav; Hashim, Audrey; Sheikh, Imran S.; Theddu, Naresh; Gaddiraju, Narendra V.; Mehrotra, Suneet; Schmitt, Kyle C.; Murray, Thomas F.; Sershen, Henry; Unterwald, Ellen M.; Davis, Franklin A.

In: Journal of Pharmacology and Experimental Therapeutics, Vol. 343, No. 2, 11.2012, p. 413-425.

Research output: Contribution to journalArticle

Reith, MEA, Ali, S, Hashim, A, Sheikh, IS, Theddu, N, Gaddiraju, NV, Mehrotra, S, Schmitt, KC, Murray, TF, Sershen, H, Unterwald, EM & Davis, FA 2012, 'Novel C-1 substituted cocaine analogs unlike cocaine or benztropine', Journal of Pharmacology and Experimental Therapeutics, vol. 343, no. 2, pp. 413-425. https://doi.org/10.1124/jpet.112.193771
Reith, Maarten E A ; Ali, Solav ; Hashim, Audrey ; Sheikh, Imran S. ; Theddu, Naresh ; Gaddiraju, Narendra V. ; Mehrotra, Suneet ; Schmitt, Kyle C. ; Murray, Thomas F. ; Sershen, Henry ; Unterwald, Ellen M. ; Davis, Franklin A. / Novel C-1 substituted cocaine analogs unlike cocaine or benztropine. In: Journal of Pharmacology and Experimental Therapeutics. 2012 ; Vol. 343, No. 2. pp. 413-425.
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