ABSTRACT
Anthranilamide analogues such as 23 are potent and highly selective muscarinic M2 antagonists that also show good oral bioavailability and in vivo activity.
Subject(s)
Muscarinic Antagonists/chemistry , Muscarinic Antagonists/pharmacology , Piperidines/chemistry , Piperidines/pharmacology , Receptor, Muscarinic M2/antagonists & inhibitors , ortho-Aminobenzoates/chemistry , Animals , Avoidance Learning/drug effects , Biochemistry/methods , Biological Availability , CHO Cells , Cricetinae , Dose-Response Relationship, Drug , Drug Evaluation, Preclinical/methods , Muscarinic Antagonists/pharmacokinetics , Rats , Structure-Activity RelationshipABSTRACT
In search of a backup M(2) muscarinic receptor antagonist to the previously reported compound 1, we discovered compound (+)-14, which showed superior oral efficacy in animal models. The improvement of oral efficacy was achieved by modulating both the molecular weight and lipophilicity of the lead compounds.
Subject(s)
Autoreceptors/antagonists & inhibitors , Central Nervous System Agents/chemical synthesis , Muscarinic Antagonists/chemical synthesis , Piperidines/chemical synthesis , Receptors, Muscarinic/drug effects , Acetylcholine/metabolism , Administration, Oral , Animals , Avoidance Learning/drug effects , Central Nervous System Agents/chemistry , Central Nervous System Agents/pharmacology , Corpus Striatum/metabolism , Humans , In Vitro Techniques , Microdialysis , Molecular Conformation , Muscarinic Antagonists/chemistry , Muscarinic Antagonists/pharmacology , Piperidines/chemistry , Piperidines/pharmacology , Rats , Receptor, Muscarinic M2 , Structure-Activity RelationshipABSTRACT
We previously reported the initial discovery of a novel class of stabilized benzylidene ketal M(2) receptor antagonists. This paper discusses new analogues consisting of benzamide modifications which not only improved M(2) receptor affinity and selectivity, but also enhanced the pharmacokinetic properties of the series. These changes led to the discovery of a highly potent and selective M(2) antagonist, which demonstrated in vivo efficacy and had good bioavailability in multiple species.
Subject(s)
Benzamides/chemistry , Benzylidene Compounds/chemistry , Benzylidene Compounds/pharmacokinetics , Muscarinic Antagonists/chemistry , Muscarinic Antagonists/pharmacology , Receptors, Muscarinic/drug effects , Acetylcholine/analysis , Acetylcholine/biosynthesis , Animals , Area Under Curve , Benzamides/pharmacology , Drug Design , Drug Evaluation, Preclinical , Humans , Microdialysis , Microsomes, Liver/drug effects , Microsomes, Liver/metabolism , Rats , Receptors, Muscarinic/metabolism , Structure-Activity RelationshipABSTRACT
A novel series of 2-(R)-methyl-substituted piperazines (e.g., 2) is described. They are potent M(2) selective ligands that have >100-fold selectivity versus the M(1) receptor. In the rat microdialysis assay, compound 14 showed significantly enchanced levels of acetylcholine after oral administration.
