Scuola in Scienze del Farmaco e dei Prodotti della Salute, Università di Camerino, Via S. Agostino 1, 62032 Camerino, Italy.
Scuola in Scienze del Farmaco e dei Prodotti della Salute, Università di Camerino, Via S. Agostino 1, 62032 Camerino, Italy.
Bioorg Med Chem. 2018 Jul 23;26(12):3502-3513. doi: 10.1016/j.bmc.2018.05.023. Epub 2018 May 17.
(+)-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.
(+)-环唑嗪 [(+)-1] 是 α-肾上腺素能受体亚型（选择性比率，α/α=13，α/α=38-39）最具选择性的拮抗剂之一。为了提高选择性，我们合成并研究了几种手性 (+)-环唑嗪类似物对 α-肾上腺素受体的阻断活性，这些类似物在羰基或氨基上具有不同的取代基，即 (-)-2、(+)-3、(-)-4-(-)-8、(+)-9。此外，我们研究了它们一些对映异构体的活性，即 (-)-1、(-)-3、(+)-6 和 (-)-9，以评估立体化学对选择性的影响。苯甲氧基羰基和甲基（4aS,8aR）类似物 (+)-3 和 (-)-6 显著提高了前体化合物的 α 选择性：分别是 4 和 14 倍对 α 亚型和 35 和 77 倍对 α 亚型。研究证实了这些分子中疏水顺式八氢喹啉部分对于与 α-肾上腺素受体建立相互作用的重要性，以及它们的 (4aS,8aR) 立体化学对于赋予 α 亚型选择性的重要性。基于对 (+)-3 化合物进行的分子建模研究，提出了这些化合物相互作用模式的假设。
