ABSTRACT
A number of analogs of the natural product himbacine were synthesized employing variations at the heterocyclic unit and the tether that links the heterocyclic unit to the tricyclic motif. Several of these analogs had M(2) affinity and M(1)/M(2) selectivity comparable to those of himbacine. The structural and stereochemical requirements of the heterocyclic unit for muscarinic binding are discussed in the light of these data.
Subject(s)
Alkaloids/pharmacology , Heterocyclic Compounds/pharmacology , Muscarinic Antagonists/chemical synthesis , Parasympatholytics/chemical synthesis , Receptors, Muscarinic/physiology , Alkaloids/chemistry , Cloning, Molecular , Furans , Heterocyclic Compounds/chemical synthesis , Humans , Molecular Structure , Muscarinic Antagonists/pharmacology , Naphthalenes , Parasympatholytics/pharmacology , Piperidines , Receptors, Muscarinic/drug effects , Recombinant Proteins/antagonists & inhibitors , Structure-Activity RelationshipABSTRACT
Low molecular weight amide derivatives were synthesized and evaluated as M(2) receptor antagonists for the treatment of Alzheimer's disease. Isopropyl amides 19 and 31 are highly potent, selective and low molecular weight M(2) receptor antagonists with structural features different from our clinical candidate 1.
Subject(s)
Amides/chemical synthesis , Muscarinic Antagonists/chemistry , Muscarinic Antagonists/metabolism , Receptor, Muscarinic M2/antagonists & inhibitors , Receptor, Muscarinic M2/metabolism , Humans , Muscarinic Antagonists/chemical synthesis , Protein Binding/physiologyABSTRACT
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
We have discovered highly potent, selective sulfide M(2) receptor antagonists with low molecular weight and different structural features compared with our phase I clinical candidate Sch 211803. Analogue 30 showed superior M(2) receptor selectivity profile over Sch 211803. More importantly, this study provided new leads for the discovery of M(2) receptor antagonists as potential drug candidates.
Subject(s)
Muscarinic Antagonists/chemical synthesis , Muscarinic Antagonists/pharmacology , Receptors, Muscarinic/drug effects , Sulfides/chemical synthesis , Sulfides/pharmacology , Binding Sites , Binding, Competitive , Muscarinic Antagonists/chemistry , Receptor, Muscarinic M1 , Receptor, Muscarinic M2 , Receptor, Muscarinic M3 , Receptor, Muscarinic M4 , Receptors, Muscarinic/metabolism , Sulfides/chemistryABSTRACT
The synthesis and muscarinic binding properties of compounds based on the 1-[4-(4-arylsulfonyl)phenylmethyl]-4-(1-aroyl-4-piperidinyl)-piperazine skeleton are described. For compounds, substituted with appropriately configured methyl groups at the benzylic center and at the piperazine 2-position, high levels of selective, M(2) subtype affinity could be obtained, particularly when the terminal N-aroyl residue was ortho-substituted.
Subject(s)
Piperazines/chemical synthesis , Piperazines/metabolism , Receptors, Muscarinic/metabolism , Binding Sites , Ligands , Molecular Structure , Piperazines/chemistry , Receptor, Muscarinic M1 , Receptor, Muscarinic M2 , 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.