Abstract
Cocaine is a highly abused drug without effective pharmacotherapies to treat it. It interacts with sigma (σ) receptors, providing logical targets for the development of medications to counteract its actions. Cocaine causes toxic and stimulant effects that can be categorized as acute effects such as convulsions and locomotor hyperactivity and subchronic effects including sensitization and place conditioning. In the present study, 3-(4-(4-cyclohexylpiperazin-1-yl)butyl)benzo[d]thiazole-2(3H)-thione (CM156), a novel compound, was developed and tested for interactions with σ receptors using radioligand binding studies. It was also evaluated against cocaine-induced effects in behavioral studies. The results showed that CM156 has nanomolar affinities for each of the σ receptor subtypes in the brain and much weaker affinities for non-σ binding sites. Pretreatment of male Swiss-Webster mice with CM156, before administering either a convulsive or locomotor stimulant dose of cocaine, led to a significant attenuation of these acute effects. CM156 also significantly reduced the expression of behavioral sensitization and place conditioning evoked by subchronic exposure to cocaine. The protective effects of CM156 are consistent with σ receptor-mediated actions. Together with previously reported findings, the data from CM156 and related σ compounds indicate that σ receptors can be targeted to alleviate deleterious actions of cocaine.
Footnotes
This study was supported by the National Institutes of Health National Institute on Drug Abuse [Grants DA011979, DA013978, DA023205] and the National Institutes of Health National Center for Research Resources [Grant P20-RR021929].
Article, publication date, and citation information can be found at http://jpet.aspetjournals.org.
doi:10.1124/jpet.109.161398.
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ABBREVIATIONS:
- NMDA
- N-methyl-d-aspartate
- NPC 16377
- 6-[6-(4-hydroxypiperidinyl)hexyloxy]-3-methylflavone
- NE-100
- N,N-dipropyl-2-[4-methoxy-3-(2-phenylethoxy)phenyl]ethylamine
- AC927
- 1-(2-phenethyl)piperidine oxalate
- CM156
- 3-(4-(4-cyclohexylpiperazin-1-yl)butyl)benzo[d]thiazole-2(3H)-thione
- D
- dopamine
- 5-HT
- 5-hydroxytryptamine (serotonin)
- TCP
- 1-[1-(2-thienyl)cyclohexyl]piperidine
- WIN35,428
- 2β-carbomethoxy-3β-(4-fluorophenyl)tropane
- AMPA
- α-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid
- AT
- angiotensin
- BK
- bradykinin
- CB
- cannabinoid
- CCK
- cholecystokinin
- ET
- endothelin
- mGluR
- metabotropic glutamate receptor
- LT
- leukotriene
- M
- muscarinic
- NK
- neurokinin
- MAO
- monoamine oxidase
- RX 821002
- 2-(2-methoxy-1,4-benzodioxan-2yl)-2-imidazoline
- CP 55940
- (1R,3R,4R)-3-[2-hydroxy-4-(1,1-dimethylheptyl)phenyl]-4-(3-hydroxypropyl)cyclohexan-1-ol
- SCH 23390
- R-(+)-7-chloro-8-hydroxy-3-methyl-1-phenyl-2,3,4, 5-tetrahydro-1H-3-benzazepine
- YM-09151-2
- nemonapride
- MDL-105,519
- 3-(2-phenyl-2-carboxyethenyl)-4,6-dichloro-1H-indole-2-carboxylic acid
- SQ 29,548
- 7-(3-((2-((phenylamino)carbonyl)hydrazino)methyl)-7-oxabicyclo(2.2.1)hept-2-yl)-5-heptenoic acid
- HU-210
- (−)-7-OH-Δ-6-tetrahydrocannabinol-dimethylheptyl
- MK801
- 5H-dibenzo[a,d]cyclohepten-5,10-imine (dizocilpine maleate)
- Ro 41-1049
- N-(2-aminoethyl)-5-(3-fluorophenyl)-4-thiazolecarboxamide
- Ro 16–6491
- N-(2-aminoethyl)-p-chlorobenzamide
- CGP 39653
- d,l-(E)-2-amino-4-propyl-5-phosphono-3-pentenoic acid
- BD1008
- N-[2-(3,4-dichlorophenyl)ethyl]-N-methyl-2-(1-pyrrolidinyl)ethylamine
- BD1047
- N-[2-(3,4-dichlorophenyl)ethyl]-N-methyl-2-(dimethylamino)ethylamine
- BD1063
- 1-[2-(3,4-dichlorophenyl)ethyl]-4-methylpiperazine.
- Received September 9, 2009.
- Accepted January 19, 2010.
- Copyright © 2010 by The American Society for Pharmacology and Experimental Therapeutics
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A Novel Substituted Piperazine, CM156, Attenuates the Stimulant and Toxic Effects of Cocaine in Mice
