Dual Alpha2C/5HT1A Receptor Agonist Allyphenyline Induces Gastroprotection and Inhibits Fundic and Colonic Contractility

Background Allyphenyline, a novel α 2 -adrenoceptor (AR) ligand, has been shown to selectively activate α 2C -adrenoceptors (AR) and 5HT 1A receptors, but also to behave as a neutral antagonist of α 2A -ARs. We exploited this unique pharmacological profile to analyze the role of α 2C -ARs and 5HT 1A receptors in the regulation of gastric mucosal integrity and gastrointestinal motility. Methods Gastric injury was induced by acidified ethanol in Wistar rats. Mucosal catalase and superoxide dismutase levels were measured by assay kits. The effect of allyphenyline on electrical field stimulation (EFS)-induced fundic and colonic contractions was determined in C57BL/6 mice. Results Intracerebroventricularly injected allyphenyline (3 and 15 nmol/rat) dose dependently inhibited the development of mucosal damage, which was antagonized by ARC 239 (α 2B/C -AR and 5HT 1A receptor antagonist), (S)-WAY 100135 (selective 5HT 1A receptor antagonist), and JP-1302 (selective α 2C -AR antagonist). This protection was accompanied by significant elevation of mucosal catalase and superoxide dismutase levels. Allyphenyline (10 −9 –10 −5 M) also inhibited EFS-induced fundic contractions, which was antagonized by ARC 239 and (S)-WAY 100135, but not by JP-1302. Similar inhibition was observed in the colon; however, in this case only ARC 239 reduced this effect, while neither selective inhibition of α 2C -ARs and 5HT 1A receptors nor genetic deletion of α 2A - and α 2B -ARs influenced it. Conclusions Activation of both central α 2C -ARs and 5HT 1A receptors contributes to the gastroprotective action of allyphenyline in rats. Its inhibitory effect on fundic contractions is mediated by 5HT 1A receptors, but neither α 2 -ARs nor 5HT 1A receptors take part in its inhibitory effect on colonic contractility in mice.