Assuntos
Fenoxibenzamina/efeitos adversos , Animais , Anti-Hipertensivos/efeitos adversos , Anti-Hipertensivos/síntese química , Anti-Hipertensivos/química , Anti-Hipertensivos/toxicidade , Testes de Carcinogenicidade , Carcinógenos/síntese química , Carcinógenos/química , Carcinógenos/farmacologia , Carcinógenos/toxicidade , Feminino , Regulamentação Governamental , Guias como Assunto , Humanos , Masculino , Camundongos , Modelos Biológicos , Exposição Ocupacional/efeitos adversos , Exposição Ocupacional/legislação & jurisprudência , Fenoxibenzamina/síntese química , Fenoxibenzamina/química , Fenoxibenzamina/toxicidade , Ratos , Estados UnidosRESUMO
A series of beta-chloroethylamines 5--18, structurally related to the irreversible alpha(1)-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 alpha-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 alpha(1)- and alpha(2)-adrenoceptors, whereas compounds 13 and 18, lacking substituents on both the phenoxy group and the oxyamino carbon chain, displayed a moderate alpha(1)-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 alpha(1)-adrenoceptor antagonists with an affinity value similar to that of PB (pIC(50) values of 7.17 and 7.06 versus 7.27). Interestingly, several compounds were able to distinguish two alpha(1)-adrenoceptor subtypes in the epididymal tissue, as revealed by the discontinuity of their inhibition curves. A mean ratio of 24:76 for these alpha(1)-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 alpha(1)-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 alpha(1)-adrenoceptor subtypes. In conclusion, we found beta-chloroethylamines that demonstrate a multiplicity of alpha(1)-adrenoceptors in the epididymal portion of young CD rat vas deferens and, as a consequence, they are possible useful tools for alpha(1)-adrenoceptor characterization.
Assuntos
Antagonistas Adrenérgicos alfa/síntese química , Etilaminas/síntese química , Fenoxibenzamina/síntese química , Antagonistas Adrenérgicos alfa/farmacologia , Animais , Dioxanos , Relação Dose-Resposta a Droga , Etilaminas/farmacologia , Concentração Inibidora 50 , Masculino , Fenoxibenzamina/farmacologia , Ligação Proteica , Ratos , Relação Estrutura-Atividade , Ducto Deferente/efeitos dos fármacosRESUMO
Crystalline perchlorate salts of aziridinium ions derived from phenoxybenzamine and dibenamine were prepared. Both aziridinium ions were tested on the rat vas deferens and found to possess alpha-adrenergic potencies which were nearly identical with those of the parent compounds. The hydrolysis rates of phenoxybenzamine and dibenamine aziridinium ions (2a,b) in physiological medium were found to be 6.0 4 x 10(-4) and 8.35 x 10(-4) sec-1, respectively. The rates of cyclization of the parent amines to 2a and 2b in aqueous medium were 1.9 x 10(-2) and 7.2 x 10(-3) sec-1, respectively. The potencies and kinetic profiles indicate that the aziridinium ion is the only active species in alpha-adrenergic blockade. Moreover, differences in potency between phenoxybenzamine and dibenamine appear to be exclusively to a difference in receptor affinity rather than to a difference in intrinsic alkylating ability.