title: Rational design of partial agonists for the muscarinic m1 acetylcholine receptor.
abstract: 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.
authors.affiliation: Institute of Pharmacy and Food Chemistry, University of Würzburg , Am Hubland, 97074 Würzburg, Germany.
authors.forename: Xinyu
authors.initials: X
authors.lastname: Chen
authors.forename: Jessika
authors.initials: J
authors.lastname: Klöckner
authors.forename: Janine
authors.initials: J
authors.lastname: Holze
authors.forename: Cornelia
authors.initials: C
authors.lastname: Zimmermann
authors.forename: Wiebke K
authors.initials: WK
authors.lastname: Seemann
authors.forename: Ramona
authors.initials: R
authors.lastname: Schrage
authors.forename: Andreas
authors.initials: A
authors.lastname: Bock
authors.forename: Klaus
authors.initials: K
authors.lastname: Mohr
authors.forename: Christian
authors.initials: C
authors.lastname: Tränkle
authors.forename: Ulrike
authors.initials: U
authors.lastname: Holzgrabe
authors.forename: Michael
authors.initials: M
authors.lastname: Decker
mesh_terms: D000818:Animals; D016466:CHO Cells; D003412:Cricetulus; D015195:Drug Design; D018721:Muscarinic Agonists / Q000138:chemical synthesis* / Q000494:pharmacology; D043643:Receptor, Muscarinic M1 / Q000819:agonists*; D013329:Structure-Activity Relationship
chemical_list: D018721:Muscarinic Agonists; D043643:Receptor, Muscarinic M1