Jpn. J. Pharmacol. 77 (3), 211-217 (1998)

Reduction of Wrap Restraint Stress-Induced Defecation by MKC-242, a Novel Benzodioxan Derivative, via 5-HT1A-Receptor Agonist Action in Rats

Michikazu Abe and Ken-Ichi Saito

Pharmaceuticals Laboratory I, Yokohama Research Center, Mitsubishi Chemical Corporation, 1000, Kamoshida, Aoba-ku, Yokohama 227-8502, Japan

Abstract: Effects of MKC-242 (5-{3-[((2S)-1,4-benzodioxan-2-ylmethyl)amino]propoxy}-1,3-benzodioxole HCI), 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.

Keywords: MKC-242, 5-HT1A receptor, Stress, Irritable bowel syndrome, Defecation

Copyrightę The Japanese Pharmacological Society 1998

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