Interstitial cells of Cajal, which express the
calcium-activated chloride channel transmembrane member 16A (TMEM16A), are an important determinant of gastrointestinal (GI) motility. We previously identified the acylaminocycloalkylthiophene class of TMEM16A inhibitors, which, following medicinal chemistry, gave analog 2-bromodifluoroacetylamino-5,6,7,8-tetrahydro-4H-cyclohepta[b]
thiophene-3-
carboxylic acid o-tolylamide (TMinh-23) with 30 nM half-maximal inhibitory concentration. Here, we tested the efficacy of TMinh-23 for inhibition of GI motility in mice. In isolated murine gastric antrum, TMinh-23 strongly inhibited spontaneous and
carbachol-stimulated rhythmic contractions. Pharmacokinetic analysis showed predicted therapeutic concentrations of TMinh-23 for at least 4 h following a single oral or intraperitoneal dose
at 10 mg/kg. Gastric emptying, as assessed following an oral bolus of
phenol red or independently by [99mTc]-
diethylenetriamine pentaacetic acid scintigraphy, was reduced by TMinh-23 by ∼60% at 20 min. Interestingly, there was little effect of TMinh-23 on baseline whole-gut transit time or time to
diarrhea induced by
castor oil. Consequent to the delay in gastric emptying, TMinh-23 administration significantly reduced the elevation in
blood sugar in mice following an oral but not intraperitoneal
glucose load. These results provide pharmacological evidence for involvement of TMEM16A in gastric emptying and suggest the utility of TMEM16A inhibition in disorders of accelerated gastric emptying, such as
dumping syndrome, and potentially for improving
glucose tolerance in
diabetes mellitus/
metabolic syndrome and enhancing satiety in
obesity.-
Cil, O., Anderson, M. O., Yen, R., Kelleher, B., Huynh, T. L., Seo, Y., Nilsen, S. P., Turner, J. R., Verkman, A. S. Slowed gastric emptying and improved oral
glucose tolerance produced by a nanomolar-potency inhibitor of
calcium-activated chloride channel TMEM16A.