A-69024: a non-benzazepine antagonist with selectivity for the dopamine D-1 receptor

A-69024 HBr, 1-(2-bromo-4,5-dimethoxybenzyl)-7-hydroxy-6-methoxy-2-methyl-1,2,3,4-tetrahydroisoquinoline hydrobromide, is a selective antagonist of the dopamine D-1 receptor. A-69024 HBr shows an apparent affinity toward the D-1 receptor (identified using [ 125I]SCH 23390) of 12.6 (4.15–38.3) nM (mean (90% CL), n = 3); the apparent affinity toward the D-2 receptor (identified using [ 3H]spiroperidol is 1 290 (1 200–1 380) nM (n = 3); using [ 125I]lysergic acid diethylamine to identify the 5-HT1C receptor gives apparent affinity of 17 800 (9 700–32 600) nM (n = 3). In assays of adenylate cyclase activity, A-69024 HBr antagonizes the D-1 receptor with a calculated affinity of 43.9 (17.5–110) nM (n = 5), while the molecule antagonizes the D-2 receptor with a calculated affinity greater than 400 nM. Behavioral studies demonstrate that A-69024 HBr (5 mg/kg s.c.) is able to block both amphetamine-induced locomotor activity and apomorphine-induced stereotypy. Furthermore, A-69024 HBr blocks SF & F 38393-, but not quinpirole-, induced rotation in rats having unilateral 6-hydroxydopamine lesions of the substantia nigra. When administered at behaviorally effective doses, A-69024 HBr neither increases the concentration of serum prolactin nor potentiates dihydroxyphenylalanine (DOPA) accumulation in the caudate-putamen of rats pretreated with the DOPA decarboxylase inhibitor NSD 1015. Because A-69024 is a dopamine receptor antagonist discriminating between the D-1 and D-2 receptors, it may be a useful research tool.