期刊
BIOORGANIC & MEDICINAL CHEMISTRY
卷 26, 期 12, 页码 3502-3513出版社
PERGAMON-ELSEVIER SCIENCE LTD
DOI: 10.1016/j.bmc.2018.05.023
关键词
alpha(1)-Adrenoceptor subtypes; alpha(1)-Adrenoceptor antagonists; alpha(1B)-Adrenoceptor selective antagonists; (+)-Cyclazosin analogues
资金
- Recordati Industry SpA Milano (Italy)
- University of Camerino (Italy)
- National Institute of General Medical Sciences (NIGMS) of the National Institutes of Health (NIH) [1R15GM119084]
- National Science Foundation [BCS-1039497]
(+)-Cyclazosin [(+)-1] is one of most selective antagonists of the alpha(1B)-adrenoceptor subtype (selectivity ratios, alpha(1B)/alpha(1A)= 13, alpha(1B)/alpha(1D)= 38-39). To improve the selectivity, we synthesized and pharmacologically studied the blocking activity against alpha(1)-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 alpha(1B) selectivity of the progenitor compound: 4 and 14 time vs. the alpha(1D) subtype and 35 and 77 times vs. the alpha(1A) subtype, respectively. The study confirmed the importance of the hydrophobic cis-octahydroquinoxaline moiety of these molecules for the establishment of interactions with the alpha(1)-adrenoceptors as well that of their (4aS, 8aR) stereochemistry to grant selectivity for the alpha(1B) subtype. Hypotheses on the mode of interaction of these compounds were advanced on the basis of molecular modeling studies performed on compound (+)-3.
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