Chiral analogues of (+)-cyclazosin as potent α1B-adrenoceptor selective antagonist. Issue 12 (23rd July 2018)

• Record Type: Journal Article
• Authors: Sagratini, Gianni; Buccioni, Michela; Marucci, Gabriella; Poggesi, Elena; Skorski, Matthew; Costanzi, Stefano; Giardinà, Dario
• Is Part Of: Bioorganic & medicinal chemistry. Volume 26:Issue 12(2018)
• Page Start: 3502
• Page End: 3513
• Publication Date: 2018-07-23
• Subjects: α1-Adrenoceptor subtypes -- α1-Adrenoceptor antagonists -- α1B-Adrenoceptor selective antagonists -- (+)-Cyclazosin analogues; Bioorganic chemistry -- Periodicals; Pharmaceutical chemistry -- Periodicals; Biochemistry -- Periodicals; Chemistry, Clinical -- Periodicals; Chemistry, Organic -- Periodicals; Chimie bio-organique -- Périodiques; Chimie pharmaceutique -- Périodiques; 615.19
• DOI: 10.1016/j.bmc.2018.05.023
• Languages: English
• ISSNs: 0968-0896

Abstract

Graphical abstract: Highlights: An improved α1B -adrenoceptor selectivity of (+)-cyclazosin analog antagonists was obtained. Compounds (+)-3 and (−)-6 have to date the highest α1B -selectivity in functional antagonism. The (4a S, 8a R ) stereochemistry of compounds resulted crucial for the α1B -selectivity. Abstract: (+)-Cyclazosin [(+)-1] is one of most selective antagonists of the α1B -adrenoceptor subtype (selectivity ratios, α1B /α1A = 13, α1B /α1D = 38–39). To improve the selectivity, we synthesized and pharmacologically studied the blocking activity against α1 -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 (4a S, 8a R ) analogues (+)-3 and (−)-6 improved in a significant way the α1B selectivity of the progenitor compound: 4 and 14 time vs. the α1D subtype and 35 and 77 times vs. the α1A subtype, respectively. The study confirmed the importance of the hydrophobic cis -octahydroquinoxaline moiety of these molecules for the establishment of interactions with the α1 -adrenoceptors as well that of their (4a S, 8a R ) stereochemistry to grant selectivity for the α1B subtype. Hypotheses on the mode of interaction of these compounds were advanced on the basis of molecular modeling studies performed on compound (+)-3 .