Rational Design of Partial Agonists for the Muscarinic M1 Acetylcholine Receptor

• Published in: Journal of medicinal chemistry 2015-01, Vol.58 (2), p.560-576
• Main Authors: Chen, Xinyu, Klöckner, Jessika, Holze, Janine, Zimmermann, Cornelia, Seemann, Wiebke K, Schrage, Ramona, Bock, Andreas, Mohr, Klaus, Tränkle, Christian, Holzgrabe, Ulrike, Decker, Michael
• Format: Article
• Language: English
• Subjects: Animals; CHO Cells; Cricetulus; Drug Design; Muscarinic Agonists - chemical synthesis; Muscarinic Agonists - pharmacology; Receptor, Muscarinic M1 - agonists; Structure-Activity Relationship
• ISSN: 0022-2623; 1520-4804
• DOI: 10.1021/jm500860w

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 of the orthosteric building blocks iperoxo and 1 linked to allosteric modulators (BQCA-derived compounds, BQCAd; TBPB-derived compound, TBPBd). Their interactions were studied with the human muscarinic acetylcholine M1-receptor (hM1) with respect to receptor binding and Gq-protein signaling. Results demonstrate that iperoxo/BQCAd (2, 3) and 1/BQCAd hybrids (4) act as M1 partial agonists, whereas 1/TBPBd hybrids (5) did not activate M1-receptors. Among the iperoxo/BQCAd-hybrids, spacer length in conjunction with the pattern of substitution tuned efficacy. Most interestingly, a model of dynamic ligand binding revealed that the spacer length of 2a and 3a controlled the probability of switch between the inactive purely allosteric and the active bitopic orthosteric/allosteric binding pose. In summary, dynamic ligand binding can be exploited in M1 receptors to design partial agonists with graded efficacy.