PT  - JOURNAL ARTICLE
AU  - Maarten E. A. Reith
AU  - Solav Ali
AU  - Audrey Hashim
AU  - Imran S. Sheikh
AU  - Naresh Theddu
AU  - Narendra V. Gaddiraju
AU  - Suneet Mehrotra
AU  - Kyle C. Schmitt
AU  - Thomas F. Murray
AU  - Henry Sershen
AU  - Ellen M. Unterwald
AU  - Franklin A. Davis
TI  - Novel C-1 Substituted Cocaine Analogs Unlike Cocaine or Benztropine
AID  - 10.1124/jpet.112.193771
DP  - 2012 Nov 01
TA  - Journal of Pharmacology and Experimental Therapeutics
PG  - 413--425
VI  - 343
IP  - 2
4099  - http://jpet.aspetjournals.org/content/343/2/413.short
4100  - http://jpet.aspetjournals.org/content/343/2/413.full
SO  - J Pharmacol Exp Ther2012 Nov 01; 343
AB  - 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.