Reduction of wrap restraint stress-induced defecation by MKC-242, a novel benzodioxan derivative, via 5-HT1A-receptor agonist action in rats.
Effects of MKC-242 (5-[3-[((2S)-1,4-benzodioxan-2-ylmethyl)amino]propoxy]-1,3-b enzodioxole HC1), a novel 5-HT1A-receptor agonist, and reference compounds on wrap restraint stress-induced defecation were evaluated in rats. Wrapping restraint stress increased defecation in rats. The increase was attenuated by putative 5-HT1A-receptor agonists, MKC-242 and 8-hydroxy-2-(di-n-propylamino)tetralin (8-OH-DPAT). The suppressive effect of MKC-242 on wrap stress-induced defecation was antagonized by prior administration of a 5-HT1A-receptor antagonist, WAY100135. MKC-242 did not affect spontaneous defecation and 5-HT-induced defecation. Diazepam and amitriptyline also significantly reduced the stress-induced defecation. However, amitriptyline showed a potent anti-cholinergic effect in the oxotremorine-induced tremor test and reduced spontaneous defecation. In contrast to MKC-242 and 8-OH-DPAT, buspirone and tandospirone tended to suppress the increase at high doses. A major metabolite of buspirone and tandospirone, 1-(2-pyrimidinyl)piperazine, antagonized the suppressive effect of MKC-242. These findings suggest that stimulation of 5-HT1A receptors reduces stress-induced defecation but not spontaneous and 5-HT-induced defecation and that MKC-242 may be useful for the treatment of irritable bowel syndrome.
Pharmaceuticals Laboratory I, Yokohama Research Center, Mitsubishi Chemical Corporation, Japan.
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Abe
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Saito
D000639:Amitriptyline / Q000494:pharmacology; D000818:Animals; D003109:Colonic Diseases, Functional / Q000188:drug therapy; D003672:Defecation / Q000187:drug effects*; D004146:Dioxanes / Q000494:pharmacology* / Q000627:therapeutic use; D004149:Dioxoles / Q000494:pharmacology* / Q000627:therapeutic use; D008297:Male; D051381:Rats; D017208:Rats, Wistar; D012149:Restraint, Physical; D017366:Serotonin Receptor Agonists / Q000494:pharmacology*; D013312:Stress, Physiological / Q000503:physiopathology* / Q000517:prevention & control
D004146:Dioxanes; D004149:Dioxoles; D017366:Serotonin Receptor Agonists; D000639:Amitriptyline; C096294:osemozotan