4-(1,2,5,6-Tetrahydro-1-alkyl-3-pyridinyl)-2-thiazolamines: a novel class of compounds with central dopamine agonist properties

Abstract

The design, synthesis, and pharmacological properties of a novel type of 4-(1,2,5,6-tetrahydro-1-alkyl-3-pyridinyl)-2-thiazolamine with dopaminergic properties are described. In particular, 4-(1,2,5,6-tetrahydro-1-propyl-3-pyridinyl)-2-thiazolamine (4c, PD 118440) and its allyl analogue (4i, 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-(1-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.