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Novel C-1 substituted cocaine analogs unlike cocaine or benztropine.
J Pharmacol Exp Ther. 2012 Nov; 343(2):413-25.JP

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.

Authors+Show Affiliations

Department of Psychiatry, New York University School of Medicine, 450 E 29th Street, Alexandria Building Room 803, New York, NY 10016, USA. maarten.reith@nyumc.orgNo affiliation info availableNo affiliation info availableNo affiliation info availableNo affiliation info availableNo affiliation info availableNo affiliation info availableNo affiliation info availableNo affiliation info availableNo affiliation info availableNo affiliation info availableNo affiliation info available

Pub Type(s)

Journal Article
Research Support, N.I.H., Extramural
Research Support, Non-U.S. Gov't

Language

eng

PubMed ID

22895898

Citation

Reith, Maarten E A., et al. "Novel C-1 Substituted Cocaine Analogs Unlike Cocaine or Benztropine." The Journal of Pharmacology and Experimental Therapeutics, vol. 343, no. 2, 2012, pp. 413-25.
Reith ME, Ali S, Hashim A, et al. Novel C-1 substituted cocaine analogs unlike cocaine or benztropine. J Pharmacol Exp Ther. 2012;343(2):413-25.
Reith, M. E., Ali, S., Hashim, A., Sheikh, I. S., Theddu, N., Gaddiraju, N. V., Mehrotra, S., Schmitt, K. C., Murray, T. F., Sershen, H., Unterwald, E. M., & Davis, F. A. (2012). Novel C-1 substituted cocaine analogs unlike cocaine or benztropine. The Journal of Pharmacology and Experimental Therapeutics, 343(2), 413-25. https://doi.org/10.1124/jpet.112.193771
Reith ME, et al. Novel C-1 Substituted Cocaine Analogs Unlike Cocaine or Benztropine. J Pharmacol Exp Ther. 2012;343(2):413-25. PubMed PMID: 22895898.
* Article titles in AMA citation format should be in sentence-case
TY - JOUR T1 - Novel C-1 substituted cocaine analogs unlike cocaine or benztropine. AU - Reith,Maarten E A, AU - Ali,Solav, AU - Hashim,Audrey, AU - Sheikh,Imran S, AU - Theddu,Naresh, AU - Gaddiraju,Narendra V, AU - Mehrotra,Suneet, AU - Schmitt,Kyle C, AU - Murray,Thomas F, AU - Sershen,Henry, AU - Unterwald,Ellen M, AU - Davis,Franklin A, Y1 - 2012/08/15/ PY - 2012/8/17/entrez PY - 2012/8/17/pubmed PY - 2013/1/1/medline SP - 413 EP - 25 JF - The Journal of pharmacology and experimental therapeutics JO - J. Pharmacol. Exp. Ther. VL - 343 IS - 2 N2 - 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. SN - 1521-0103 UR - https://www.unboundmedicine.com/medline/citation/22895898/Novel_C_1_substituted_cocaine_analogs_unlike_cocaine_or_benztropine_ L2 - http://jpet.aspetjournals.org/cgi/pmidlookup?view=long&pmid=22895898 DB - PRIME DP - Unbound Medicine ER -