Isothiocyanate derivatives of 9-[3-(cis-3,5-dimethyl-1-piperazinyl)propyl]carbazole (rimcazole): irreversible ligands for the dopamine transporter

Journal of Medicinal Chemistry
S M HusbandsA H Newman

Abstract

Cocaine has been reported to bind to the dopamine transporter in a biphasic fashion, and it has been hypothesized that the low-affinity component may play a modulatory role in cocaine's psychomotor stimulant effects. In an effort to gain further insight into the roles of the two sites, we have prepared a series of irreversible ligands based on rimcazole (9-[3-(cis-3,5-dimethyl-1-piperazinyl)propyl]carbazole, 2), a compound that has been postulated to bind only to the low-affinity site. The alkylating moiety (isothiocyanate) is attached to the distal nitrogen of the piperazine ring via alkyl chains of varying lengths or directly attached to one of the aromatic groups. It was found that substitution on the piperazine nitrogen caused an initial decrease in affinity that was recovered as the alkyl chain length increased. Importantly, the analogue 16, with the highest affinity for the dopamine transporter (DAT), binds in a monophasic and irreversible manner, as evidenced by the greatly diminished binding of [3H]WIN 35,428 in tissue that had been preincubated with the ligand and then thoroughly washed using centrifugation. The dose-dependent reduction in Bmax was accompanied by a concentration-related decrease in KD values. This shif...Continue Reading

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Citations

May 14, 2003·European Journal of Pharmacology·Jonathan L KatzAmy Hauck Newman
Jun 5, 2003·European Journal of Pharmacology·Rae R MatsumotoDaniel J Brackett
Sep 6, 2002·Pharmacology, Biochemistry, and Behavior·S M RawlsMartin W Adler
Jun 2, 2007·Biochemical Pharmacology·Vishakantha MurthySteven R Childers
May 16, 2009·Bioorganic & Medicinal Chemistry·David J LapinskyRoxanne A Vaughan
May 22, 2008·The Journal of Pharmacology and Experimental Therapeutics·Vishakantha MurthySteven R Childers
Dec 10, 2015·Current Protocols in Pharmacology·Uyen B Chu, Arnold E Ruoho
Feb 24, 2004·CNS Drug Reviews·Deborah L GilmoreRae R Matsumoto

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