Slowed gastric emptying and improved oral glucose tolerance produced by a nanomolar-potency inhibitor of calcium-activated chloride channel TMEM16A
| Autor: | Tony Huynh, Bryan Kelleher, Jerrold R. Turner, Robert Yen, Onur Cil, Marc O. Anderson, Alan S. Verkman, Youngho Seo, Steven P. Nilsen |
|---|---|
| Jazyk: | angličtina |
| Rok vydání: | 2019 |
| Předmět: |
0301 basic medicine
Blood Glucose Blood sugar chemistry.chemical_element Pharmacology Calcium Biochemistry 03 medical and health sciences symbols.namesake Mice 0302 clinical medicine Bolus (medicine) Chlorides Chloride Channels Diabetes mellitus Genetics medicine Animals Humans Chloride Channel Agonists Molecular Biology Anoctamin-1 Gastric emptying Chemistry Research Glucose Tolerance Test medicine.disease Interstitial cell of Cajal Neoplasm Proteins 030104 developmental biology Glucose Gastric Emptying Chloride channel symbols Dumping syndrome Female Gastrointestinal Motility 030217 neurology & neurosurgery Biotechnology |
| Zdroj: | FASEB J |
| Popis: | 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 (TM(inh)-23) with 30 nM half-maximal inhibitory concentration. Here, we tested the efficacy of TM(inh)-23 for inhibition of GI motility in mice. In isolated murine gastric antrum, TM(inh)-23 strongly inhibited spontaneous and carbachol-stimulated rhythmic contractions. Pharmacokinetic analysis showed predicted therapeutic concentrations of TM(inh)-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 [(99m)Tc]-diethylenetriamine pentaacetic acid scintigraphy, was reduced by TM(inh)-23 by ∼60% at 20 min. Interestingly, there was little effect of TM(inh)-23 on baseline whole-gut transit time or time to diarrhea induced by castor oil. Consequent to the delay in gastric emptying, TM(inh)-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. |
| Databáze: | OpenAIRE |
| Externí odkaz: |
|