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.
Footnotes
This work was supported by the National Institutes of Health National Institute on Drug Abuse [Grants R01 DA019676, P30 DA13429]; the National Institutes of Health National Institute on Mental Health [Grant R01 MH083840]; and a grant from the Commonwealth of Pennsylvania, Ben Franklin Technology Development Authority.
Article, publication date, and citation information can be found at http://jpet.aspetjournals.org.
↵ The online version of this article (available at http://jpet.aspetjournals.org) contains supplemental material.
ABBREVIATIONS:
- SAR
- structure-activity relationship
- ANOVA
- analysis of variance
- β-CFT
- 2β-carbomethoxy-3β-(4-fluorophenyl)tropane
- CPP
- conditioned place preference
- DA
- dopamine
- DAT
- DA transporter
- hDAT
- human DAT
- DMSO
- dimethyl sulfoxide
- HEK
- human embryonic kidney
- LeuT
- leucine transporter
- MOE
- Molecular Operating Environment
- NET
- norepinephrine transporter
- NSS
- neurotransmitter/sodium symporter
- PDSP
- Psychoactive Drug Screening Program
- RTI-15
- 3ß-benzoyloxy-8-methyl-8-azabicyclo (3.2.1) octane-2-carboxylic acid phenyl ester
- SBFI
- sodium-binding benzofuran isophthalate
- SERT
- serotonin transporter
- TM
- transmembrane
- TUI
- triple uptake inhibitor.
- Received February 28, 2012.
- Accepted August 2, 2012.
- Copyright © 2012 by The American Society for Pharmacology and Experimental Therapeutics
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