ABSTRACT
Piperidine analogues of our previously described piperazine muscarinic antagonists are described. Piperidine analogues show a distinct structure-activity relationship (SAR) that differs from comparable piperazines. Compounds with high selectivity and improved potency for the M2 receptor have been identified. The lead compound, 12b, increases acetylcholine release in vivo. Compounds of this class may be useful for the treatment of cognitive disorders such as Alzheimer's disease (AD).
Subject(s)
Muscarinic Antagonists/chemical synthesis , Muscarinic Antagonists/pharmacology , Piperidines/chemical synthesis , Piperidines/pharmacology , Receptors, Muscarinic/metabolism , Acetylcholine/metabolism , Animals , Corpus Striatum/drug effects , Corpus Striatum/metabolism , Molecular Structure , Muscarinic Antagonists/chemistry , Piperidines/chemistry , Rats , Receptor, Muscarinic M2 , Structure-Activity RelationshipABSTRACT
Benzylidene ketal derivatives were investigated as selective M2 receptor antagonists for the treatment of Alzheimer's disease. Compound 10 was discovered to have subnanomolar M2 receptor affinity and 100-fold selectivity against other muscarinic receptors. Also, 10 demonstrated in vivo efficacy in rodent models of muscarinic activity and cognition.
