Chen, Xinyu and Kloeckner, Jessika and Holze, Janine and Zimmermann, Cornelia and Seemann, Wiebke K. and Schrage, Ramona and Bock, Andreas and Mohr, Klaus and Traenkle, Christian and Holzgrabe, Ulrike and Decker, Michael (2015) Rational Design of Partial Agonists for the Muscarinic M-1 Acetylcholine Receptor. JOURNAL OF MEDICINAL CHEMISTRY, 58 (2). pp. 560-576. ISSN 0022-2623, 1520-4804
Full text not available from this repository. (Request a copy)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 M-1-receptor (hM(1)) with respect to receptor binding and G(q)-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 M-1-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 M-1 receptors to design partial agonists with graded efficacy.
| Item Type: | Article |
|---|---|
| Uncontrolled Keywords: | PROTEIN-COUPLED RECEPTORS; ALLOSTERIC MODULATION; BITOPIC LIGANDS; ACTIVATION; SITE; INTERNALIZATION; MECHANISMS; EMPHASIS; DISEASE; ANALOGS; |
| Subjects: | 600 Technology > 615 Pharmacy |
| Divisions: | Chemistry and Pharmacy > Institute of Pharmacy |
| Depositing User: | Dr. Gernot Deinzer |
| Date Deposited: | 25 Jul 2019 11:17 |
| Last Modified: | 25 Jul 2019 11:17 |
| URI: | https://pred.uni-regensburg.de/id/eprint/6083 |
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