TY - JOUR T1 - A Novel Selective Muscarinic Acetylcholine Receptor Subtype 1 Antagonist Reduces Seizures without Impairing Hippocampus-Dependent Learning JF - Molecular Pharmacology JO - Mol Pharmacol SP - 356 LP - 368 DO - 10.1124/mol.109.056531 VL - 76 IS - 2 AU - Douglas J. Sheffler AU - Richard Williams AU - Thomas M. Bridges AU - Zixiu Xiang AU - Alexander S. Kane AU - Nellie E. Byun AU - Satyawan Jadhav AU - Mathew M. Mock AU - Fang Zheng AU - L. Michelle Lewis AU - Carrie K. Jones AU - Colleen M. Niswender AU - Charles D. Weaver AU - Craig W. Lindsley AU - P. Jeffrey Conn Y1 - 2009/08/01 UR - http://molpharm.aspetjournals.org/content/76/2/356.abstract N2 - Previous studies suggest that selective antagonists of specific subtypes of muscarinic acetylcholine receptors (mAChRs) may provide a novel approach for the treatment of certain central nervous system (CNS) disorders, including epileptic disorders, Parkinson's disease, and dystonia. Unfortunately, previously reported antagonists are not highly selective for specific mAChR subtypes, making it difficult to definitively establish the functional roles and therapeutic potential for individual subtypes of this receptor subfamily. The M1 mAChR is of particular interest as a potential target for treatment of CNS disorders. We now report the discovery of a novel selective antagonist of M1 mAChRs, termed VU0255035 [N-(3-oxo-3-(4-(pyridine-4-yl)piperazin-1-yl)propyl)-benzo[c][1,2,5]thiadiazole-4 sulfonamide]. Equilibrium radioligand binding and functional studies demonstrate a greater than 75-fold selectivity of VU0255035 for M1 mAChRs relative to M2-M5. Molecular pharmacology and mutagenesis studies indicate that VU0255035 is a competitive orthosteric antagonist of M1 mAChRs, a surprising finding given the high level of M1 mAChR selectivity relative to other orthosteric antagonists. Whole-cell patch-clamp recordings demonstrate that VU0255035 inhibits potentiation of N-methyl-d-aspartate receptor currents by the muscarinic agonist carbachol in hippocampal pyramidal cells. VU0255035 has excellent brain penetration in vivo and is efficacious in reducing pilocarpine-induced seizures in mice. We were surprised to find that doses of VU0255035 that reduce pilocarpine-induced seizures do not induce deficits in contextual freezing, a measure of hippocampus-dependent learning that is disrupted by nonselective mAChR antagonists. Taken together, these data suggest that selective antagonists of M1 mAChRs do not induce the severe cognitive deficits seen with nonselective mAChR antagonists and could provide a novel approach for the treatment certain of CNS disorders. ER -