Synthesis and α-adrenoreceptor blocking properties of phenoxybenzamine-related (2-chloroethyl)-(2,3-dihydrobenzo-[1,4]dioxin-2-ylmethyl)-(2-phenoxyethyl) amines

Abstract A series of β-chloroethylamines, structural hybrids of WB 4101, a competitive α 1 -adrenoreceptor antagonist, and phenoxybenzamine, an irreversible α-adrenoreceptor antagonist, has been synthesized and tested in isolated rat vas deferens α-adrenoreceptors. Although, for all compounds, apparent blocking potency and α 1 -selectivity are quite similar to those of phenoxybenzamine, affinity values calculated by taking into account the actual concentration of aziridinium ion in solution, reveal that compounds bearing a 1,4-benzodioxan-2-ylmethyl moiety, display a significantly higher potency for both α 1 - and α 2 -adrenoreceptors than compounds having a benzyl group. In addition, two of the compounds, having both methyl and methoxy groups in their structure, show a marked discontinuity in the α 1 -adrenoreceptor concentration-inhibition curve, with a plateau in the range 30–100 nM. Stereochemical aspects are also shown to play an important role in the binding. The biological results suggest that the two irreversible antagonists may be able to discriminate between two α 1 -adrenoreceptor subtypes, which are both involved in the noradrenaline-induced contraction of the epididymal portion of rat vas deferens.