Vol. 296, Issue 2, 338-344, February 2001

Dinapsoline: Characterization of a D₁ Dopamine Receptor Agonist in a Rat Model of Parkinson's Disease

Amit G. Gulwadi, Carolyn D. Korpinen, Richard B. Mailman, David E. Nichols, Sing-Yuen Sit and Matthew T. Taber

Neuroscience/Genitourinary Drug Discovery, Bristol-Myers Squibb Inc., Wallingford, Connecticut (A.G.G., C.D.K., S.-Y.S., M.T.T.); Neuroscience Center & Departments of Psychiatry, Pharmacology, and Medicinal Chemistry, University of North Carolina School of Medicine, Chapel Hill, North Carolina (R.B.M.); and Department of Medicinal Chemistry and Molecular Pharmacology, Purdue University School of Pharmacy, West Lafayette, Indiana (D.E.N.)

Dinapsoline is a new potent, full agonist at D₁ dopamine receptors with limited selectivity relative to D₂ receptors. The efficacy of this compound was assessed in rats with unilateral 6-hydroxydopamine lesions of the medial forebrain bundle, a standard rat model of Parkinson's disease. Dinapsoline produced robust contralateral rotation after either subcutaneous or oral administration. This rotational behavior was attenuated markedly by the D₁ receptor antagonist SCH-23390, but not by the D₂ receptor antagonist raclopride. During a chronic 14-day treatment period in which rats received dinapsoline either once or twice a day, dinapsoline did not produce tolerance (in fact, some sensitization of the rotational response was observed in one experiment). Because dinapsoline shows less D₁:D₂ selectivity in vitro than other D₁ agonists, the contribution of D₂ activity to tolerance was assessed. Chronic daily cotreatment with dinapsoline and raclopride did not enable the development of tolerance to chronic dinapsoline treatment. In contrast, when dinapsoline was administered by osmotic minipump, rapid tolerance was observed. To explore further the contribution of D₁ and D₂ receptors to tolerance, experiments were performed with the selective D₁ agonist A-77636. Daily dosing with A-77636 rapidly produced complete tolerance, as previously observed, whereas coadministration of the D₂ agonist quinpirole plus A-77636 failed to either delay or prevent tolerance. Taken together, these results indicate that the development of tolerance to D₁ receptor agonists is influenced by the pattern of drug exposure but not by the D₁:D₂ selectivity of the agonist.