PHARMACOLOGICAL PROFILE OF THE DOPAMINE PARTIAL AGONIST, (+/--PD-128483 AND ITS ENANTIOMERS

(+/-)-PD 128483, {(+/-)-4,5,5a,6,7,8-hexahydro-6-methylthiazolo[4,5-f]-quinolin-2-amine, maleate (1:1)}, is a racemic compound that is a p.o. active dopamine (DA) partial agonist that has DA autoreceptor agonist effects and displays antipsychotic-like activity in preclinical tests. In in vitro receptor binding assays, (+/-)-PD 128483 and its enantiomers bound selectively to DA D-2 receptors vs. DA D-1 receptors and showed no affinity for adrenergic alpha-1 or serotonin1A receptors, but had affinity for adrenergic alpha-2 receptors. In tests of DA agonist effects, including reversal of the tau-butyrolactone-stimulated increase in brain dopa synthesis in striatum and inhibition of DA neuronal firing, the rank order of efficacy was (+)-PD 128483 > (+/-)-PD 128483 > (-)-PD 128483. (+/-)-PD 128483 and (+)-PD 128483 inhibited, whereas (-)-PD 128483 increased, brain DA synthesis in normal rats. (+/-)-PD 128483 and (-)-PD 128483 inhibited spontaneous locomotion in rats and did not produce locomotor stimulation or stereotypies. In contrast, (+)-PD 128483 inhibited locomotor activity at low doses, but at relatively high doses increased locomotion and induced stereotypy in rats. (-)-PD 128483 consistently inhibited Sidman avoidance responding in squirrel monkeys. (+/-)-PD 128483 inhibited Sidman avoidance responding in one group of monkeys, but had minimal effects in another group. (+)-PD 128483 did not inhibit avoidance responding. In squirrel or cebus monkeys sensitized to the acute dystonic effects of haloperidol, only (-)-PD 128483 induced extrapyramidal dysfunction. These results indicate that (+)-PD 128483 is a DA partial agonist which produces DA autoreceptor agonist effects and has a preclinical behavioral profile suggestive of antipsychotic activity.