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 odioxan-2-ylmethyl)amino]propoxy}-1,3-benzodioxole HCl), 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 attenu ated 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 administra tion of a 5-HT1A-receptor antagonist, WAY100135. MKC-242 did not affec t spontaneous defecation and 5-HT-induced defecation. Diazepam and ami triptyline also significantly reduced the stress-induced defecation. H owever, amitriptyline showed a potent anti-cholinergic effect in the o xotremorine-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 buspiron e and tandospirone, 1-(2-pyrimidinyl)piperazine, antagonized the suppr essive 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 tre atment of irritable bowel syndrome.