Discovery of the first highly M5-preferring muscarinic acetylcholine receptor ligand, an M5 positive allosteric modulator derived from a series of 5-trifluoromethoxy N-benzyl isatins.
This report describes the discovery and initial characterization of the first positive allosteric modulator of muscarinic acetylcholine receptor subtype 5 (mAChR5 or M5). Functional HTS, identified VU0119498, which displayed micromolar potencies for potentiation of acetylcholine at M1, M3, and M5 receptors in cell-based Ca(2+) mobilization assays. Subsequent optimization led to the discovery of VU0238429, which possessed an EC(50) of approximately 1.16 microM at M5 with >30-fold selectivity versus M1 and M3, with no M2 or M4 potentiator activity.
Vanderbilt Program in Drug Discovery, Department of Pharmacology and Chemistry, Vanderbilt University Medical Center, Nashville, TN 37232-0697, USA.
Thomas M
TM
Bridges
Joy E
JE
Marlo
Colleen M
CM
Niswender
Carrie K
CK
Jones
Satyawan B
SB
Jadhav
Patrick R
PR
Gentry
Hyekyung C
HC
Plumley
C David
CD
Weaver
P Jeffrey
PJ
Conn
Craig W
CW
Lindsley
D000494:Allosteric Regulation / Q000502:physiology; D000818:Animals; D016466:CHO Cells; D006224:Cricetinae; D003412:Cricetulus; D007510:Isatin / Q000031:analogs & derivatives* / Q000138:chemical synthesis / Q000494:pharmacology*; D051379:Mice; D043642:Receptor, Muscarinic M5 / Q000187:drug effects* / Q000378:metabolism
D043642:Receptor, Muscarinic M5; C541699:VU 01119498; D007510:Isatin