4-(1,2,5,6-TETRAHYDRO-1-ALKYL-3-PYRIDINYL)-2-THIAZOLAMINES - A NOVEL CLASS OF COMPOUNDS WITH CENTRAL DOPAMINE AGONIST PROPERTIES

The design, synthesis, and pharmacological properties of a novel type of 4-(1, 2, 5, 6-tetrahydro-l-alkyl-3-pyridinyl)-2-thiazolamine with dopaminergic properties are described. In particular, 4-(1, 2, 5, 6-tetrahydro-l-propyl-3-pyridinyl)-2-thiazolamine (4c, PD 118440) and its allyl analogue (4c, PD 120697) have been identified as orally active dopamine (DA) agonists with pronounced central nervous system effects in tests that include [3H]-haloperidol and [3H]-N-propylnorapomorphine binding, inhibition of striatal DA synthesis, inhibition of DA neuronal firing, inhibition of spontaneous locomotor activity, and reversal of reserpine-induced depression in rats. The DA autoreceptor selectivity of these heterocyclic analogues of 3-(l-propyl-3-piperidinyl)phenol (3-PPP) was also evaluated. In this series, DA agonist activity was found to be highly dependent on the size of the N-alkyl substituent, the saturation level of the six-membered ring, and the mode of attachment of the 2-aminothiazole ring. © 1990, American Chemical Society. All rights reserved.