Synthesis And Studies On Chiral Antagonists Of M Receptors

Chirality is one of the essence attributes of nature. Recently the chiral NCEs (new chemical entities) is the new reaserch yield in search of novel drugs. Because many vital diseases such as Parkinsonian syndromes, Alzheimer's disease, chronic obstructive pulmonary disease(COPD) and irritable bowel syndrome are associated with M receptors, more and more attention has been paid to the research on M receptor antagonists. However, the lack of receptor subtype selectivity or organ specificity of M receptor antagonists limited their clinical application. It has been well established that the receptor selectivity and organ specificity not only depends on the chemical properties but also the stereochemical properties.Penehyclidine Hydrochloride (PH) is a new anti-cholinerigic drug invested by the Institute of Pharmacology and Toxicology AMMS,which has anti-muscarinic activities and retains potent central and peripheral anti-cholinerigic activities.The clinic results demonstrate that PH has the good curative effect for the pesticides poison of organic phosphorus. There are two chiral carbons in PH, so there are four optical isomers of PH. And there are distinguished differences in the pharmacological activities of the four optical isomers. In this report, the four optical isomers were asymmetricly synthesized, and we studied the stereochemistry, pharmacology and toxicology of the chiral M receptor antagonists. For the study of pharmacokinetics, some PH analogues were designed and synthesized, then, the differences in M receptor affinity and toxicology among these enationmers will be...