A novel selective muscarinic acetylcholine receptor subtype 1 antagonist reduces seizures without impairing hippocampus-dependent learning.
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 M(1) 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 M(1) 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 M(1) mAChRs relative to M(2)-M(5). Molecular pharmacology and mutagenesis studies indicate that VU0255035 is a competitive orthosteric antagonist of M(1) mAChRs, a surprising finding given the high level of M(1) 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 M(1) 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.
Sheffler
Douglas J
DJ
Department of Pharmacology, Vanderbilt University Medical Center, Nashville, TN 37232, USA.
Williams
Richard
R
Bridges
Thomas M
TM
Xiang
Zixiu
Z
Kane
Alexander S
AS
Byun
Nellie E
NE
Jadhav
Satyawan
S
Mock
Mathew M
MM
Zheng
Fang
F
Lewis
L Michelle
LM
Jones
Carrie K
CK
Niswender
Colleen M
CM
Weaver
Charles D
CD
Lindsley
Craig W
CW
Conn
P Jeffrey
PJ
D000818:Animals; D001667:Binding, Competitive / Q000187:drug effects; D016466:CHO Cells; D006224:Cricetinae; D003412:Cricetulus; D004305:Dose-Response Relationship, Drug; D004594:Electrophysiology; D006624:Hippocampus / Q000378:metabolism*; D020128:Inhibitory Concentration 50; D007858:Learning / Q000502:physiology*; D008297:Male; D051379:Mice; D015394:Molecular Structure; D018727:Muscarinic Antagonists / Q000737:chemistry / Q000378:metabolism*; D018408:Patch-Clamp Techniques; D051381:Rats; D017207:Rats, Sprague-Dawley; D043643:Receptor, Muscarinic M1 / Q000378:metabolism*; D012640:Seizures / Q000378:metabolism*; D012680:Sensitivity and Specificity; D013449:Sulfonamides / Q000037:antagonists & inhibitors / Q000493:pharmacokinetics; D013830:Thiadiazoles / Q000037:antagonists & inhibitors / Q000493:pharmacokinetics
D018727:Muscarinic Antagonists; C542801:N-(3-oxo-3-(4-(pyridin-4-yl)piperazin-1-yl)propyl)benzo(c)(1,2,5)thiadiazole-4-sulfonamide; D043643:Receptor, Muscarinic M1; D013449:Sulfonamides; D013830:Thiadiazoles