Structure-Based Design and Discovery of New M-2 Receptor Agonists

Journal article
(Original article)

Publication Details

Author(s): Fish I, Stößel A, Eitel K, Valant C, Albold S, Hübner H, Möller D, Clark MJ, Sunahara RK, Christopoulos A, Shoichet BK, Gmeiner P
Journal: Journal of Medicinal Chemistry
Publication year: 2017
Volume: 60
Journal issue: 22
Pages range: 9239-9250
ISSN: 0022-2623


Muscarinic receptor agonists are characterized by apparently strict restraints on their tertiary or quaternary amine and their distance to an ester or related center. On the basis of the active state crystal structure of the muscarinic M-2 receptor in complex with iperoxo, we explored potential agonists that lacked the highly conserved functionalities of previously known ligands. Using structure-guided pharmacophore design followed by docking, we found two agonists (compounds 3 and 17), out of 19 docked and synthesized compounds, that fit the receptor well and were predicted to form a hydrogen-bond conserved among known agonists. Structural optimization led to compound 28, which was 4-fold more potent than its parent 3. Fortified by the discovery of this new scaffold, we sought a broader range of chemotypes by docking 2.2 million fragments, which revealed another three micromolar agonists unrelated either to 28 or known muscarinics. Even pockets as tightly defined and as deeply studied as that of the muscarinic reveal opportunities for the structure-based design and the discovery of new chemotypes.

FAU Authors / FAU Editors

Eitel, Katrin
Lehrstuhl für Pharmazeutische Chemie
Gmeiner, Peter Prof. Dr.
Lehrstuhl für Pharmazeutische Chemie
Hübner, Harald Dr.
Lehrstuhl für Pharmazeutische Chemie
Weikert, Dorothee Dr.
Lehrstuhl für Pharmazeutische Chemie
Stößel, Anne Dr.
Lehrstuhl für Pharmazeutische Chemie

Additional Organisation
Emil-Fischer-Zentrum (Emil Fischer Center)

External institutions with authors

Monash University
University of California, San Diego
University of California San Francisco (UCSF)

How to cite

Fish, I., Stößel, A., Eitel, K., Valant, C., Albold, S., Hübner, H.,... Gmeiner, P. (2017). Structure-Based Design and Discovery of New M-2 Receptor Agonists. Journal of Medicinal Chemistry, 60(22), 9239-9250.

Fish, Inbar, et al. "Structure-Based Design and Discovery of New M-2 Receptor Agonists." Journal of Medicinal Chemistry 60.22 (2017): 9239-9250.


Last updated on 2018-10-08 at 23:55