Muscarinic receptors are known to play important biological roles and are drug targets for several human diseases. In a pilot study, novel muscarinic antagonists were synthesized and used as chemical probes to obtain additional information of the muscarinic pharmacophore. The design of these ligands made use of current orthosteric and allosteric models of drug-receptor interactions together with chemical motifs known to achieve muscarinic receptor selectivity. This approach has led to the discovery of several non-competitive muscarinic ligands that strongly bind at a secondary receptor site. These compounds were found to be non-competitive antagonists that completely abolished carbachol activation in functional assays. Several of these compounds antagonized functional response to carbachol with great potency at M1 and M4 than at the rest of receptor subtypes.

Department of Neurochemistry Institute of Physiology of the Academy of Sciences of the Czech Republic Prague Czech Republic

Department of Physical Sciences Barry University Miami Shores FL USA

Eshelman School of Pharmacy University of North Carolina Chapel Hill NC USA

References provided by Crossref.org

Guanidine Derivatives: How Simple Structural Modification of Histamine H3R Antagonists Has Led to the Discovery of Potent Muscarinic M2R/M4R Antagonists

Novel M2 -selective, Gi -biased agonists of muscarinic acetylcholine receptors

Applications and limitations of fitting of the operational model to determine relative efficacies of agonists

Novel long-acting antagonists of muscarinic ACh receptors