title: Evaluation of 1,2,5-thiadiazoles as modulators of M₁/M₅ muscarinic receptor subtypes.
abstract: Studies have demonstrated the presence of allosteric binding sites on each of the muscarinic acetylcholine receptor (mAChR) subtypes. Since most drugs targeting muscarinic receptors bind to the highly conserved orthosteric binding site, they fail to achieve appreciable subtype selectivity. Targeting non-conserved allosteric sites may provide a new way of enhancing selectivity for individual subtypes of muscarinic receptor. Tetra(ethyleneglycol)(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, CDD-0304 (10), was found to be a M₁/₂/₄ selective muscarinic agonist and might prove useful in treating the symptoms associated with schizophrenia (J. Med. Chem.2003, 46, 4273). It was hypothesized that the observed subtype selectivity demonstrated by 10 may be due to its ability to function as a bitopic ligand (J. Med. Chem.2006, 49, 7518). To further investigate this possibility, a novel series of compounds was synthesized using a 1,2,5-thiadiazole moiety along with varying lengths of a polyethylene glycol linker and terminal groups, for evaluation as potential allosteric modulators of muscarinic receptors. Preliminary biological studies were performed using carbachol to stimulate M₁ and M₅ receptors. No significant agonist activity was observed at either M₁ or M₅ receptors for any of the compounds. Compound 18, 2-(4-methoxy-1,2,5-thiadiazol-3-yloxy)-N,N-dimethylethanamine fumarate (CDD-0361F) was found to block the effects of carbachol at M5 muscarinic receptors.
authors.affiliation: Department of Medicinal and Biological Chemistry, MS 1015, The University of Toledo, College of Pharmacy and Pharmaceutical Sciences, 3000 Arlington Ave., Toledo, OH 43614, United States.
authors.forename: Aditya
authors.initials: A
authors.lastname: Maheshwari
authors.affiliation: Department of Medicinal and Biological Chemistry, MS 1015, The University of Toledo, College of Pharmacy and Pharmaceutical Sciences, 3000 Arlington Ave., Toledo, OH 43614, United States.
authors.forename: P S S
authors.initials: PS
authors.lastname: Rao
authors.affiliation: Department of Medicinal and Biological Chemistry, MS 1015, The University of Toledo, College of Pharmacy and Pharmaceutical Sciences, 3000 Arlington Ave., Toledo, OH 43614, United States; Department of Pharmacology, MS 1015, The University of Toledo, College of Pharmacy and Pharmaceutical Sciences, 3000 Arlington Ave., Toledo, OH 43614, United States. Electronic address: william.messer@utoledo.edu.
authors.forename: William S
authors.initials: WS
authors.lastname: Messer
mesh_terms: D000494:Allosteric Regulation / Q000187:drug effects; D004305:Dose-Response Relationship, Drug; D006801:Humans; D015394:Molecular Structure; D043643:Receptor, Muscarinic M1 / Q000037:antagonists & inhibitors*; D043642:Receptor, Muscarinic M5 / Q000037:antagonists & inhibitors*; D013329:Structure-Activity Relationship; D013830:Thiadiazoles / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology*
chemical_list: D043643:Receptor, Muscarinic M1; D043642:Receptor, Muscarinic M5; D013830:Thiadiazoles
keywords: Drug abuse; M(5) antagonist; Muscarinic receptor