Evidence for dopamine D1 receptor involvement in the reinforcing and other behavioral effects of cocaine and other psychomotor stimulant drugs suggests that D1 mechanisms are rational targets for the development of anti-stimulant medications. This program of medicinal chemistry and pharmacology is intended to continue development of novel dopamine D1 partial agonists with 1) oral bioavailability and long duration of action to advance as candidate therapeutics and 2) unique pharmacological characteristics (e.g., D5 vs. D1 selectivity, 'atypical' profile of action) to serve as research tools. The pharmacology of newly synthesized compounds will be established in radioligand binding experiments, studies of adenylyl cyclase stimulation, and in vivo procedures to determine potency, duration of action, and behavioral effects in rats and primates. Lead compounds will be further studied in cocaine self-administration procedures as a preclinical test of anti-stimulant efficacy. Two major results are expected of this program. First, one or more dopamine D1 partial agonists with minimal side effects will be forwarded as candidate therapeutic(s) for the treatment of psychomotor stimulant abuse. Secondly, new research tools will be developed to study the roles of subtypes of D1- family receptors and of adenylyl cyclase in the mediation of abuse-related and other behavioral effects of stimulant drugs.
At present, there are no uniformly effective medications for the treatment of cocaine abuse and dependence, and this remains one of our most serious drug abuse problems. The development of such effective medications would have significant commercial application both for development by the pharmaceutical industry and by the government. The compounds proposed for synthesis are all novel and patentable, thus increasing their commercial value.
