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