Design and synthesis of potential M1 muscarinic acetylcholine receptor dualsteric modulator

Charles University in Prague, Faculty of Pharmacy in Hradci Králové Department of: Inorganic and Organic chemistry Consultant: Prof. Dr. Ulrike Holzgrabe, PharmDr. Jaroslav Roh, Ph.D. Student: Petr Průša Title of Thesis: Design and synthesis of potential M1 muscarinic acetylcholine receptor dualsteric modulator Dualsteric ligands can modulate activity of receptors connected with G-proteins, also known as G- protein coupled receptor. These ligands are interesting for their use as pharmacological tools to clarify activity-induced conformational transitions. Moreover, dualsteric ligands can serve like a concept for design of new drugs. It was already prove that dualsteric compounds containing orthosteric ligand, which can act as agonist or antagonist, and allosteric part, which act as address determining target receptor via own selectivity, have affected affinity to receptor. Further, dualsteric binding can serve to introduce receptor subtype selectivity. Muscarinic acetylcholine receptors are related to G-proteins. Until now five subtypes of these receptors (usually marked as M1 - M5) are known. Activation of single muscarinic acetylcholine receptors subtypes induce different replies. Muscarinic acetylcholine receptors are widely represent in entire organism and are important targets for some drugs...