Design And Synthesis Of Selective M3 Receptor Antagonists

Muscarinic receptor (M receptor) is one of important cholinergic receptors in human organisms. It distributes extensively in human central and peripheral nerve systems, myocardium, smooth muscle and glandular organs and involves in various physiological function. M3 receptor is one of muscarinic receptor subtypes which were classified by the difference of gene expression and pharmacology. By inhibiting or stimulating M3 receptor, the smooth muscle contraction and gland secretion can be controlled by effector cells which are located at postganglionic parasympathetic nerve fiber. Designing and synthesizing compounds that can inhibit M3 receptor become a significant strategy to develop drugs for diseases such as Over Active Bladder and Chronic Obstructive Pulmonary Disease.The objective of this research is to develop novel compounds that have relatively activity and possess independent intellectual property by designing and synthesizing selective M3 receptor antagonist. As a preparaptory work for the discovery and development of M3 receptor antagonist drug, this research will provide a good platform for the subsequent research. Achievement of this research is as follows:1. As a drug intermediate of solifenacin, 1-phenyl-1,2,3,4- terohydroisoquinoline was synthesized and the synthesis process was improved.2. Homology models of human M3 receptor was built by homology modeling, while the reliability of the models was evaluated by their RMSD value. Two considerably accurate final models were obtained with their RMSD value around 2.6. Those homology models will be the basis of de novel drug design.3. Pharmacophore models of M3 receptor antagonists were built based on seven drugs with high activity. Every model has twelve pharmacophores. Database searching was then performed based on the obtained models. This searching hited fifteen compounds which contain five commercial or clinical drugs. Study on synthesis of novel compounds 3-(1,2,2,2-tetraphenylethoxy)quinuclidine and 3,4-diphenyl-1- (quinuclidin-3-yl)butan-2-one were performed. Key intermediates 1,2,2,2-tetraphenyl ethanone and 3,4-diphenyl-1- (quinuclidin -3-yl)butan-2-one were synthesized. All of the synthesized compounds were confirmed by 1HNMR.