Rational Design of Partial Agonists for the Muscarinic M1 Acetylcholine Receptor
作者： Xinyu Chen , Jessika Klöckner , Janine Holze , Cornelia Zimmermann , Wiebke K. Seemann
DOI: 10.1021/JM500860W
关键词: Stereochemistry 、 Acetylcholine receptor 、 Partial agonist 、 Chemistry 、 Receptor 、 Muscarinic acetylcholine receptor 、 Allosteric regulation 、 Muscarinic acetylcholine receptor M5 、 Rational design
摘要: Aiming to design partial agonists for a G-protein-coupled receptor based on dynamic ligand binding, we synthesized three different series of bipharmacophoric ligands composed the orthosteric building blocks iperoxo and 1 linked allosteric modulators (BQCA-derived compounds, BQCAd; TBPB-derived compound, TBPBd). Their interactions were studied with human muscarinic acetylcholine M1-receptor (hM1) respect binding Gq-protein signaling. Results demonstrate that iperoxo/BQCAd (2, 3) 1/BQCAd hybrids (4) act as M1 agonists, whereas 1/TBPBd (5) did not activate M1-receptors. Among iperoxo/BQCAd-hybrids, spacer length in conjunction pattern substitution tuned efficacy. Most interestingly, model revealed 2a 3a controlled probability switch between inactive purely active bitopic orthosteric/allosteric pose. In summary, can be exploit...
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