Sumanirole, a highly dopamine D2-selective receptor agonist:: In vitro and in vivo pharmacological characterization and efficacy in animal models of Parkinson's disease

The purpose of this study is to demonstrate that sumanirole is a novel dopamine receptor agonist with high in vitro and in vivo selectivity for the D-2 receptor subtype. Sumanirole, (R)-5,6-dihydro-5-(methylamino)-4H- imidazo[4,5,1-ij] quinolin-2(1H)one (Z)-2-butenedioate (1:1), is unique; it has greater than 200-fold selectivity for the D-2 receptor subtype versus the other dopamine receptor subtypes in radioligand binding assays. In cell-based assays, sumanirole is a fully efficacious agonist, with EC50 values between 17 and 75 nM. In animals, sumanirole elicits many physiological responses attributed to D-2-like receptor function. In rats, sumanirole is a full agonist for elevation of striatal acetylcholine levels (ED50 = 12.1 mu mol/kg i.p.). Sumanirole s.c. dose dependently decreased plasma prolactin levels and depressed dopamine neuron firing rates in the substantia nigra pars compacta with an ED50 of 2.3 mu mol/kg i.v. This high selectivity for D-2 receptors translates into excellent locomotor stimulant activity in animal models of Parkinson's disease. In reserpinized, alpha-methyl-para-tyrosine-treated rats, sumanirole caused a significant and sustained increase in horizontal activity at doses >= 12.5 mu mol/kg s.c. In unilateral 6-hydroxydopamine-lesioned rats, sumanirole caused profound, sustained rotational behavior and was substantially more efficacious than any other agonist tested. Sumanirole-stimulated rotational behavior was blocked by the dopamine receptor antagonist haloperidol. Sumanirole dose dependently improved disability scores and locomotor activities of two of three 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine-lesioned monkeys. In summary, sumanirole is the first published selective D-2 receptor agonist. The compound has activity in animal models of dopamine hypofunction and has a high level of efficacy in animal models of Parkinson's disease.