RT Journal Article
SR Electronic
T1 An approach to discovering novel muscarinic M1 receptor positive allosteric modulators with potent cognitive improvement and minimized gastrointestinal dysfunction
JF Journal of Pharmacology and Experimental Therapeutics
JO J Pharmacol Exp Ther
FD American Society for Pharmacology and Experimental Therapeutics
SP jpet.117.243774
DO 10.1124/jpet.117.243774
A1 Emi Kurimoto
A1 Satoru Matsuda
A1 Yuji Shimizu
A1 Yuu Sako
A1 Takao Mandai
A1 Takahiro Sugimoto
A1 Hiroki Sakamoto
A1 Haruhide Kimura
YR 2017
UL http://jpet.aspetjournals.org/content/early/2017/10/12/jpet.117.243774.abstract
AB Activation of muscarinic M1 receptor (M1R) is a promising approach for improving cognitive impairment in Alzheimer's disease. However, an M1 selective positive allosteric modulator (PAM), benzyl quinolone carboxylic acid (BQCA), at 30 mg/kg, induced diarrhea in wild-type mice, but not in M1R knock-out mice. Moreover, BQCA (0.1-1000 nM) augmented electric field stimulation (EFS) -induced ileum contraction in an in vitro Magnus assay. Thus, we decided to establish a drug-screening strategy to discover novel M1 PAMs producing potent cognitive improvement with minimized gastrointestinal (GI) dysfunction. We assessed PAM parameters of various M1 PAMs with ≥ 100-fold selectivity over other muscarinic receptor subtypes by using in vitro binding and functional analysis. Evaluation of these M1 PAMs in the Magnus assay revealed a significant correlation between % of ileum contractions at 1 μM and their α-value, a PAM parameter associated with the binding cooperativity between acetylcholine and M1 PAM. M1 PAMs with lower α-value showed lower impact on EFS-induced ileum contraction. Next, we characterized in vivo profiles of two M1 PAMs: compound A (log α = 1.18) and compound B (log α = 3.30). Compound A, at 30 mg/kg, significantly improved scopolamine-induced cognitive deficits without prominent signs of diarrhea at up to 1000 mg/kg in mice. In contrast, compound B, at 10 mg/kg, showed both significant improvement of scopolamine-induced cognitive deficits and severe diarrhea. Thus, fine adjustment of the α-values could be a key to discovering M1 PAMs yielding potent cognitive improvement with a lower risk of GI effects.