Structure-activity relationships among novel phenoxybenzamine-related β-chloroethylamines

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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 (pIC50values 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. © 2002 Elsevier Science Ltd. All rights reserved.




Giardinà, D., Crucianelli, M., Angeli, P., Buccioni, M., Gulini, U., Marucci, G., … Melchiorre, C. (2002). Structure-activity relationships among novel phenoxybenzamine-related β-chloroethylamines. Bioorganic and Medicinal Chemistry, 10(5), 1291–1303.

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