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

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Abstract

Background

Allyphenyline, a novel α2-adrenoceptor (AR) ligand, has been shown to selectively activate α2C-adrenoceptors (AR) and 5HT1A receptors, but also to behave as a neutral antagonist of α2A-ARs. We exploited this unique pharmacological profile to analyze the role of α2C-ARs and 5HT1A 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 (α2B/C-AR and 5HT1A receptor antagonist), (S)-WAY 100135 (selective 5HT1A receptor antagonist), and JP-1302 (selective α2C-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 α2C-ARs and 5HT1A receptors nor genetic deletion of α2A- and α2B-ARs influenced it.

Conclusions

Activation of both central α2C-ARs and 5HT1A receptors contributes to the gastroprotective action of allyphenyline in rats. Its inhibitory effect on fundic contractions is mediated by 5HT1A receptors, but neither α2-ARs nor 5HT1A receptors take part in its inhibitory effect on colonic contractility in mice.

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Acknowledgments

Our research was supported by the Hungarian Scientific Research Fund (OTKA PD 109602). The authors wish to thank Mrs. I. Szalai for her technical assistance.

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    1. Department of Pharmacology and Pharmacotherapy, Faculty of Medicine, Semmelweis University, Nagyvárad tér 4., Budapest, 1089, Hungary

      Zoltán S. Zádori, Ágnes Fehér, Viktória E. Tóth, Mahmoud Al-Khrasani, László Köles, Szabina Sipos & Klára Gyires

    2. School of Pharmacy, Medicinal Chemistry Unit, University of Camerino, via S. Agostino 1, 62032, Camerino, Italy

      Fabio Del Bello & Maria Pigini

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    1. Zoltán S. Zádori
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    Zoltán S. Zádori and Ágnes Fehér have equally contributed to this work.

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    Zádori, Z.S., Fehér, Á., Tóth, V.E. et al. Dual Alpha2C/5HT1A Receptor Agonist Allyphenyline Induces Gastroprotection and Inhibits Fundic and Colonic Contractility. Dig Dis Sci 61, 1512–1523 (2016). https://doi.org/10.1007/s10620-015-4026-9

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