Structure–Activity relationships among novel phenoxybenzamine-Related β-Chloroethylamines Original Research Article

A series of β-chloroethylamines 5–18, structurally related to the irreversible α1-adrenoceptor antagonist phenoxybenzamine [PB, N-benzyl-N-(2-chloroethyl)-N-(1-methyl-2-phenoxyethyl)amine hydrochloride, 1] and the competitive antagonist WB4101 [N-(2,3-dihydro-1,4-benzodioxin-2-ylmethyl)-N-[2-(2,6-dimethoxyphenoxy)ethyl]amine hydrochloride, 2], were synthesized and evaluated for their activity at α-adrenoceptors of the epididymal and the prostatic portion of young CD rat vas deferens. All compounds displayed irreversible antagonist activity. Most of them showed similar antagonism at both α1- and α2-adrenoceptors, whereas compounds 13 and 18, lacking substituents on both the phenoxy group and the oxyamino carbon chain, displayed a moderate α1-adrenoceptor selectivity (10–35 times), which was comparable to that of PB. Compounds 14 and 15, belonging to the benzyl series and bearing, respectively, a 2-ethoxyphenoxy and a 2-i-propoxyphenoxy moiety, were the most potent α1-adrenoceptor antagonists with an affinity value similar to that of PB (pIC50 values of 7.17 and 7.06 versus 7.27). Interestingly, several compounds were able to distinguish two α1-adrenoceptor subtypes in the epididymal tissue, as revealed by the discontinuity of their inhibition curves. A mean ratio of 24:76 for these α1-adrenoceptors was determined from compounds 8–10, 12, and 15–17. Furthermore, compounds 9, 10, 12, 16a, and 16b showed higher affinity towards the minor population of receptors, whereas compounds 8, 15, and 17 preferentially inhibited the major population of α1-adrenoceptors. In addition, selected pharmacological experiments demonstrated the complementary antagonism of the two series of compounds and their different, preferential affinity for one of the two α1-adrenoceptor subtypes. In conclusion, we found β-chloroethylamines that demonstrate a multiplicity of α1-adrenoceptors in the epididymal portion of young CD rat vas deferens and, as a consequence, they are possible useful tools for α1-adrenoceptor characterization.