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.
AUTHORS
Bridges
TMThomas M ,
Marlo
JE Joy E ,
Niswender
CM Colleen M ,
Jones
CK Carrie K ,
Jadhav
SB Satyawan B ,
Gentry
PR Patrick R ,
Plumley
HC Hyekyung C ,
Weaver
CD C David ,
Conn
PJ P Jeffrey ,
Lindsley
CW Craig W .
Journal of medicinal chemistry. 2009 6 11; 52(11).
3445-8
- PMID: 19438238[PubMed].
- PMCID: PMC3875304.
- NIHMSID: NIHMS212577
ABSTRACT
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.