Pyridinylpiperazines, a new class of selective .alpha.2-adrenoceptor antagonists

A series of 1-(2-pyridinyl)piperazine derivatives was synthesized and evaluated for adrenergic activity. In vitro activity was assessed through the antagonism of clonidine's effect in the rat, isolated, field-stimulated vas deferens and by the displacement of [3H]clonidine from membrane binding sites of calf cerebral cortex. Antagonism of clonidine-induced mydriasis in the rat was used as an in vivo assay. Several members of the series proved to be potent, selective alpha 2-adrenoceptor antagonists. 1-(3-Fluoro-2-pyridinyl)piperazine was more potent than either yohimbine or rauwolscine in displacement of [3H]clonidine and had a higher affinity for this binding site (alpha 2) than for the [3H]prazosin site (alpha 1). In vivo, the 3-F derivative was more potent than the reference standards in reversing clonidine-induced mydriasis. None of the members of this series was more selective or potent than rauwolscine in antagonizing clonidine in the rat vas deferens.