A68930 - A POTENT AGONIST SELECTIVE FOR THE DOPAMINE-D1 RECEPTOR

A68930, (1R,3S)-1-aminomethyl-5,6-dihydroxy-3-phenylisochroman HCl, is a potent (EC50 = 2.5 nM), partial (intrinsic activity = 66% of dopamine) agonist in the fish retina dopamine-sensitive adenylate cyclase model of the D1 dopamine receptor. In the rat caudate-putamen model of the D1 dopamine receptor, A68930 is a potent (EC50 = 2.1 nM) full agonist. In contrast, A68930 is a much weaker (EC50 = 3920 nM) full agonist in a biochemical model of the dopamine D2 receptor. The orientation of the 3-phenyl substituent in the molecule is critical for the affinity and selectivity of the molecule towards the dopamine D1 receptor. A68930 also displays weak alpha-2-agonist activity but the molecule is virtually inactive at the alpha-1- and beta-adrenoceptors. When tested in rats bearing a unilateral 6-OHDA lesion of the nigro-neostriatal neurons, A68930 elicits prolonged (> 20 h) contralateral turning that is antagonized by dopamine D1 receptor selective doses of SCH 23390 but not by D2 receptor selective doses of haloperidol. In this lesioned rat model, A68930 increases 2-deoxyglucose accumulation in the lesioned substantia nigra, pars reticulata. When tested in normal rats, A68930 elicits hyperactivity and, at higher doses, produces a forelimb clonus.