application): A program of medicinal chemistry and pharmacology is proposed for the synthesis and evaluation of novel dopamine D1 receptor ligands to treat addiction to cocaine and other psychomotor stimulant drugs of abuse. The impetus for this proposal comes from preliminary findings in preclinical studies showing that the D1 partial agonist SKF 83959 a 1- aryl-3-benzazepine may decrease abuse-related effects of cocaine with little side-effect liability. The applicant proposes to synthesize novel derivatives of racemic SKF 83959 that may have increased potency and longer duration of action. These will include enantiomers of SKF 83959; cogeners with protected hydroxy functions on the catechol moiety, and halogenated or alkylated derivatives. The pharmacology of newly synthesized ligands will be established with: 1) in vitro procedures to determine dopamine D1 receptor selectivity in radioligand binding experiments and 2) in vivo procedures to determine potency and duration of action in a primate species and to further evaluate agonist efficacy in behavioral assays of eyeblinking and reversal of catalepsy induced by dopamine D1 receptor blockade, This research is expected to result in one or more dopamine D1 partial agonists with increased duration of action and minimal side effects for further development as candidate anti-cocaine medications.
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 problems. The development of such effective medications would have significant commercial application both for development by the pharmaceutical industry and by the government.
