biostudies-literatureChayka A?stav organick? chemie a biochemie Akademie ved Cesk? republiky10135-10151https://www.ebi.ac.uk/biostudies/studies/S-EPMC11215778biostudies-literatureUnknown67(12)Yohimbine, a natural indole alkaloid and a nonselective adrenoceptor antagonist, possesses potential benefits in treating inflammatory disorders and sepsis. Nevertheless, its broader clinical use faces challenges due to its low receptor selectivity. A structure-activity relationship study of novel yohimbine analogues identified amino esters of yohimbic acid as potent and selective ADRA2A antagonists. Specifically, amino ester <b>4n</b>, in comparison to yohimbine, showed a 6-fold higher ADRA1A/ADRA2A selectivity index (SI > 556 for <b>4n</b>) and a 25-fold higher ADRA2B/ADRA2A selectivity index. Compound <b>4n</b> also demonstrated high plasma and microsomal stability, moderate-to-low membrane permeability determining its limited ability to cross the blood-brain barrier, and negligible toxJournal of medicinal chemistryStructure-Based Drug Design of ADRA2A Antagonists Derived from Yohimbine.PMC11215778RVO 61388963Janeba ZKuzmova EStrmen TOsifova ZBroz BKozak JTloust'ova EDracinsky MChayka AMertlikova-Kaiserova HDvorakova ACesnek MfalseStructure-Based Drug Design of ADRA2A Antagonists Derived from Yohimbine.Yohimbine, a natural indole alkaloid and a nonselective adrenoceptor antagonist, possesses potential benefits in treating inflammatory disorders and sepsis. Nevertheless, its broader clinical use faces challenges due to its low receptor selectivity. A structure-activity relationship study of novel yohimbine analogues identified amino esters of yohimbic acid as potent and selective ADRA2A antagonists. Specifically, amino ester <b>4n</b>, in comparison to yohimbine, showed a 6-fold higher ADRA1A/ADRA2A selectivity index (SI > 556 for <b>4n</b>) and a 25-fold higher ADRA2B/ADRA2A selectivity index. Compound <b>4n</b> also demonstrated high plasma and microsomal stability, moderate-to-low membrane permeability determining its limited ability to cross the blood-brain barrier, and negligible tox2024-01-01T00:00:00Z2024 Jun2026-05-29T10:04:43.579Z2025-04-07T02:11:49.74ZS-EPMC112157783885706710.1021/acs.jmedchem.4c00323