RESUMO
To acquire more information about the so-called "muscarinic subsite", compound 4 was synthesized and tested. The results show that in comparison with deoxamuscarine (23) the muscarinic potency of 4 on M2 and M3 subtypes is not significantly altered by the presence of an epoxidic function, which confirms the donor-acceptor hydrogen bonding character of this receptive site. Conversely, there is a negative influence on the transduction processes. In addition, a second hydroxylic function bound on the carbon carrying the terminal methyl of the fourth substituent on the nitrogen dramatically affects the muscarinic behavior; the resulting compounds (11-14) lack any agonist or antagonist activity.
Assuntos
Compostos Bicíclicos Heterocíclicos com Pontes , Compostos Bicíclicos com Pontes/síntese química , Parassimpatomiméticos/síntese química , Compostos de Amônio Quaternário/síntese química , Animais , Compostos Bicíclicos com Pontes/farmacologia , Cobaias , Técnicas In Vitro , Masculino , Parassimpatomiméticos/farmacologia , Compostos de Amônio Quaternário/farmacologia , Receptores Muscarínicos/efeitos dos fármacos , Estereoisomerismo , Relação Estrutura-AtividadeRESUMO
Several prazosin-related compounds have been synthesized and evaluated for their blocking activity toward alpha-adrenoreceptors. The structural modification performed on the prazosin structure included the replacement of the piperazine ring with 2,3-dialkylpiperazine or 1,2-cyclohexanediamine moieties to characterize a lipophilic binding pocket in the alpha 1-adrenoreceptor surface. Cyclohexanediamine derivatives 3-6 were almost devoid of potency and selectivity, whereas dialkylpiperazine compounds 7-14 showed high affinity and selectivity toward alpha 1-adrenoreceptors. The cis derivative 13 (cyclazosin) was the most potent and selective with an alpha 1/alpha 2 selectivity ratio value of 7800. The particular trend of antagonist activity within cis/trans stereoisomeric compounds not only supports the presence of a lipophilic binding area on alpha 1-adrenoreceptor surface but also suggests that the lipophilic pocket is endowed with a well-defined size and spatial orientation. The most active compound of the series, 13, was tested also in vivo for antihypertensive activity on spontaneously hypertensive rats. It showed an interesting long-lasting hypotensive effect, very similar to that of doxazosin, which was statistically significant 12 h after oral administration.