A series of beta-chloroethylamines 5–18, structurallyrelated to the irreversible a1-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 activityat a-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 alpha1- and alpha2-adrenoceptors, whereas compounds 13 and 18, lacking substituents on both the phenoxy group and the oxyamino carbon chain, displayed a moderate alpha1-adrenoceptor selectivity(10–35 times), which was comparable to that of PB. Compounds 14 and 15, belonging to the benzyl series and bearing, respectively, alpha 2-ethoxyphenoxy and a 2-i-propoxyphenoxy moiety, were the most potent alpha1-adrenoceptor antagonists with an affinityvalue similar to that of PB (pIC50 values of 7.17 and 7.06 versus 7.27). Interestingly, several compounds were able to distinguish two a1-adrenoceptor subtypes in the epididymal tissue, as revealed by the discontinuity of their inhibition curves. A mean ratio of 24:76 for these a1-adrenoceptors was determined from compounds 8–10, 12, and 15–17. Furthermore, compounds 9, 10, 12, 16a, and 16b showed higher affinitytowards the minor population of receptors, whereas compounds 8, 15, and 17 preferentiallyinhibited the major population of alpha1-adrenoceptors. In addition, selected pharmacological experiments demonstrated the complementaryantagonism of the two series of compounds and their different, preferential affinity for one of the two alpha 1-adrenoceptor subtypes. In conclusion, we found beta-chloroethylamines that demonstrate a multiplicity of alpha1-adrenoceptors in the epididymal portion of young CD rat vas deferens and, as a consequence, they are possible useful tools for alpha1-adrenoceptor characterization.
Structure-Activity Relatioships Among Novel Phenoxybenzamine-Related Beta-Chloroethylamines.
GIARDINA', Dario;ANGELI, Piero;MARUCCI, Gabriella;BUCCIONI, Michela;GULINI, Ugo;SAGRATINI, Gianni;
2002-01-01
Abstract
A series of beta-chloroethylamines 5–18, structurallyrelated to the irreversible a1-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 activityat a-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 alpha1- and alpha2-adrenoceptors, whereas compounds 13 and 18, lacking substituents on both the phenoxy group and the oxyamino carbon chain, displayed a moderate alpha1-adrenoceptor selectivity(10–35 times), which was comparable to that of PB. Compounds 14 and 15, belonging to the benzyl series and bearing, respectively, alpha 2-ethoxyphenoxy and a 2-i-propoxyphenoxy moiety, were the most potent alpha1-adrenoceptor antagonists with an affinityvalue similar to that of PB (pIC50 values of 7.17 and 7.06 versus 7.27). Interestingly, several compounds were able to distinguish two a1-adrenoceptor subtypes in the epididymal tissue, as revealed by the discontinuity of their inhibition curves. A mean ratio of 24:76 for these a1-adrenoceptors was determined from compounds 8–10, 12, and 15–17. Furthermore, compounds 9, 10, 12, 16a, and 16b showed higher affinitytowards the minor population of receptors, whereas compounds 8, 15, and 17 preferentiallyinhibited the major population of alpha1-adrenoceptors. In addition, selected pharmacological experiments demonstrated the complementaryantagonism of the two series of compounds and their different, preferential affinity for one of the two alpha 1-adrenoceptor subtypes. In conclusion, we found beta-chloroethylamines that demonstrate a multiplicity of alpha1-adrenoceptors in the epididymal portion of young CD rat vas deferens and, as a consequence, they are possible useful tools for alpha1-adrenoceptor characterization.I documenti in IRIS sono protetti da copyright e tutti i diritti sono riservati, salvo diversa indicazione.
