Abstract
Despite a wealth of information on cocaine-like compounds, there is no information on cocaine analogues with substitutions at C-1. Here, we report on (R)-(-)-cocaine analogues with various C-1 substituents: methyl (2), ethyl (3), n-propyl (4), n-pentyl (5) and phenyl (6). Analogue 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 analogues, however, stimulated mouse locomotor activity, in contrast to cocaine. Pharmacokinetic assays showed compound 2 occupied mouse brain as rapidly as cocaine itself; moreover, 2 was behaviorally active in mice in the forced swim test model of depression and the conditioned place preference test. Analogue 2 was a weaker inhibitor of voltage-dependent Na+ channels than cocaine, though 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 analogues are not cocaine-like in that they are not stimulatory in vivo. However, they are not benztropine-like in binding mechanism and appear to interact with the DAT similarly to cocaine. The present data warrant further consideration of these novel cocaine analogues for antidepressant or cocaine substitution potential.
- Received February 28, 2012.
- Revision received August 1, 2012.
- Accepted August 2, 2012.
- The American Society for Pharmacology and Experimental Therapeutics