Chiral analogues of (+)-cyclazosin as potent α-adrenoceptor selective antagonist.

(+)-Cyclazosin [(+)-1] is one of most selective antagonists of the α-adrenoceptor subtype (selectivity ratios, α/α = 13, α/α = 38-39). To improve the selectivity, we synthesized and pharmacologically studied the blocking activity against α-adrenoceptors of several homochiral analogues of (+)-cyclazosin featuring different substituents on the carbonyl or amine groups, namely (-)-2, (+)-3, (-)-4-(-)-8, (+)-9. Moreover, we studied the activity of some their opposite enantiomers, namely (-)-1, (-)-3, (+)-6, and (-)-9, to evaluate the influence of stereochemistry on selectivity. The benzyloxycarbonyl and methyl (4aS,8aR) analogues (+)-3 and (-)-6 improved in a significant way the α selectivity of the progenitor compound: 4 and 14 time vs. the α subtype and 35 and 77 times vs. the α subtype, respectively. The study confirmed the importance of the hydrophobic cis-octahydroquinoxaline moiety of these molecules for the establishment of interactions with the α-adrenoceptors as well that of their (4aS,8aR) stereochemistry to grant selectivity for the α subtype. Hypotheses on the mode of interaction of these compounds were advanced on the basis of molecular modeling studies performed on compound (+)-3.