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Mechanisms of selective modulation of individual subtypes of muscarinic receptors

Altered muscarinic signalling is frequently involved in neurological and psychiatric diseases as well as diseases of internal organs. To target a particular condition, selective modulation of individual muscarinic subtypes is necessary to avoid side effects. High homology of the orthosteric binding site among all muscarinic subtypes makes a finding of orthosteric ligands that bind selectively to individual muscarinic subtypes virtually unattainable. Allosteric ligands modulate binding of orthosteric ligands and functional response to agonists from less-conserved sites on the receptor. Dualsteric ligands employ both orthosteric and allosteric sites. The aim of this project is structure-guided development of novel selective allosteric and dualsteric ligands.