.alpha.-Adrenoreceptor reagents. 1. Synthesis of some 1,4-benzodioxans as selective presynaptic .alpha.2-adrenoreceptor antagonists and potential antidepressants

Abstract

The rational design of RX 781094, 2-(1,4-benzodioxan-2-yl)-2-imidazoline hydrochloride, a new potent and selective antagonist of .alpha.2-adrenoreceptors, is discussed. A compound that acts as an antagonist at presynaptic .alpha.2-adrenoreceptors could be an effective and novel treatment of depression because of its ability to increase the concentration of norepinephrine at central receptor sites. The effects of substituents in the aromatic and imidazoline rings were examined in rice and rats as well as the replacement of the imidazoline ring by an amidine function or by other heterocyclic ring systems. None of these derivatives are as potent or selective as RX 781094; although some do display a degree of selectivity as antagonists. Some derivatives possessed agonist properties that favored the postsynaptic site. Compounds possessing presynaptic .alpha.2-adrenoreceptor antagonist and postsynaptic .alpha.1-adrenoreceptor partial agonist properties were also obtained, and these derivatives could be considered as potential antimigraine agents.