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NEUROPHARMACOLOGY

Sumanirole, a Highly Dopamine D₂-Selective Receptor Agonist: In Vitro and in Vivo Pharmacological Characterization and Efficacy in Animal Models of Parkinson's Disease

Pfizer, Inc., Kalamazoo, Michigan (R.B.M., R.M.H.); Department of Pharmacology and Toxicology, Michigan State University, East Lansing, Michigan (K.J.L.); and Centre de Recherche en Neurosciences, Laval University Hospital, Sainte-Foy, Québec, Canada (P.J.B.)

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, -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.

Address correspondence to: Dr. Robert B. McCall, Pfizer, Inc., 301 Henrietta St., 7251-209-305, Kalamazoo, MI 49007. E-mail: robert.b.mccall{at}pfizer.com

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