Universität zu Köln

Chen, Xinyu, Kloeckner, Jessika, Holze, Janine, Zimmermann, Cornelia, Seemann, Wiebke K., Schrage, Ramona, Bock, Andreas ORCID: 0000-0002-6344-6494, Mohr, Klaus, Traenkle, Christian, Holzgrabe, Ulrike ORCID: 0000-0002-0364-7278 and Decker, Michael ORCID: 0000-0002-6773-6245 (2015). Rational Design of Partial Agonists for the Muscarinic M-1 Acetylcholine Receptor. J. Med. Chem., 58 (2). S. 560 - 577. WASHINGTON: AMER CHEMICAL SOC. ISSN 1520-4804

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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:	Journal Article
Creators:	Creators Email ORCID ORCID Put Code Chen, Xinyu UNSPECIFIED UNSPECIFIED UNSPECIFIED Kloeckner, Jessika UNSPECIFIED UNSPECIFIED UNSPECIFIED Holze, Janine UNSPECIFIED UNSPECIFIED UNSPECIFIED Zimmermann, Cornelia UNSPECIFIED UNSPECIFIED UNSPECIFIED Seemann, Wiebke K. UNSPECIFIED UNSPECIFIED UNSPECIFIED Schrage, Ramona UNSPECIFIED UNSPECIFIED UNSPECIFIED Bock, Andreas UNSPECIFIED orcid.org/0000-0002-6344-6494 UNSPECIFIED Mohr, Klaus UNSPECIFIED UNSPECIFIED UNSPECIFIED Traenkle, Christian UNSPECIFIED UNSPECIFIED UNSPECIFIED Holzgrabe, Ulrike UNSPECIFIED orcid.org/0000-0002-0364-7278 UNSPECIFIED Decker, Michael UNSPECIFIED orcid.org/0000-0002-6773-6245 UNSPECIFIED
URN:	urn:nbn:de:hbz:38-414436
DOI:	10.1021/jm500860w
Journal or Publication Title:	J. Med. Chem.
Volume:	58
Number:	2
Page Range:	S. 560 - 577
Date:	2015
Publisher:	AMER CHEMICAL SOC
Place of Publication:	WASHINGTON
ISSN:	1520-4804
Language:	English
Faculty:	Unspecified
Divisions:	Unspecified
Subjects:	no entry
Uncontrolled Keywords:	Keywords Language PROTEIN-COUPLED RECEPTORS; ALLOSTERIC MODULATION; BITOPIC LIGANDS; ACTIVATION; SITE; INTERNALIZATION; MECHANISMS; EMPHASIS; DISEASE; ANALOGS Multiple languages Chemistry, Medicinal Multiple languages
URI:	http://kups.ub.uni-koeln.de/id/eprint/41443