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J Med Chem ; 49(25): 7518-31, 2006 Dec 14.
Article in English | MEDLINE | ID: mdl-17149881

ABSTRACT

As part of a continuing effort to design and synthesize highly selective muscarinic agonists for different muscarinic receptor subtypes, several tetra(ethylene glycol)(3-methoxy-1,2,5-thiadiazol-4-yl) [3-(1-methyl-1,2,5,6-tetrahydropyrid-3-yl)-1,2,5-thiadiazol-4-yl] ether (1) analogues were prepared and characterized. Different analogues were synthesized having hydrophilic spacers of di-, tri-, tetra-, penta(ethylene glycol) and tri(propylene glycol) separating the 1,2,5,6-tetrahydropyridine ring from the terminal heterocycle, which was either a 1,2,5-thiadiazole or 1,2,4-thiadiazole ring. Chimeric receptor and molecular modeling studies also were conducted to determine how the ligands interact with muscarinic receptors. The studies revealed that varying the distance of the terminal thiadiazole and the positioning of the methoxy group can increase binding affinity for certain muscarinic receptor subtypes (at M(2) for 13d and M(4) for 1) and enhance functional efficacy at M(4) receptors for 13e and 18b. Moreover, compound 1 exhibited antipsychotic activity as assessed by reversal of apomorphine-induced sensory motor gating deficits, suggesting potential utility in the treatment of schizophrenia.


Subject(s)
Antipsychotic Agents/chemical synthesis , Muscarinic Agonists/chemical synthesis , Piperidines/chemical synthesis , Receptors, Muscarinic/drug effects , Recombinant Fusion Proteins/metabolism , Thiadiazoles/chemical synthesis , Animals , Antipsychotic Agents/chemistry , Antipsychotic Agents/pharmacology , Cell Line , Cyclic AMP/biosynthesis , Drug Design , Humans , Hydrolysis , Ligands , Mice , Models, Molecular , Muscarinic Agonists/chemistry , Muscarinic Agonists/pharmacology , Mutagenesis, Site-Directed , Mutation , Phosphatidylinositols/metabolism , Piperidines/chemistry , Piperidines/pharmacology , Radioligand Assay , Receptors, Muscarinic/genetics , Receptors, Muscarinic/physiology , Recombinant Fusion Proteins/genetics , Structure-Activity Relationship , Thiadiazoles/chemistry , Thiadiazoles/pharmacology
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