%0 Journal Article %A Robert B. McCall %A Keith J. Lookingland %A Paul J. Bédard %A Rita M. Huff %T Sumanirole, a Highly Dopamine D2-Selective Receptor Agonist: In Vitro and in Vivo Pharmacological Characterization and Efficacy in Animal Models of Parkinson's Disease %D 2005 %R 10.1124/jpet.105.084202 %J Journal of Pharmacology and Experimental Therapeutics %P 1248-1256 %V 314 %N 3 %X 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 D2 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 D2 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 D2-like receptor function. In rats, sumanirole is a full agonist for elevation of striatal acetylcholine levels (ED50 = 12.1 μmol/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 μmol/kg i.v. This high selectivity for D2 receptors translates into excellent locomotor stimulant activity in animal models of Parkinson's disease. In reserpinized, α-methyl-para-tyrosine-treated rats, sumanirole caused a significant and sustained increase in horizontal activity at doses ≥12.5 μmol/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 D2 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. The American Society for Pharmacology and Experimental Therapeutics %U https://jpet.aspetjournals.org/content/jpet/314/3/1248.full.pdf