α-Adrenoreceptor reagents. I. Synthesis of some 1,4-benzodioxans as selective presynaptic α2-adrenoreceptor antagonists and potential antidepressants

Article abstract of DOI:10.1021/jm00360a008

The rational design of RX 781094, 2-(1,4-benzodioxan-2-yl)-2-imidazoline hydrochloride (5), a new potent and selective antagonist of α₂-adrenoreceptors, is discussed. A compound that acts as an antagonist at presynaptic α₂-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 have been examined, 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 5, although some do display a degree of selectivity as antagonists. Some derivatives were found to possess agonist properties that, with the exception of 23, favored the postsynaptic site. Compounds 9, 12, 16, 21, 30, and 51 possessing presynaptic α₂-adrenoreceptor antagonist and postsynaptic α₁-adrenoreceptor partial agonist properties were also obtained, and these derivatives could be considered as potential antimigraine agents.