Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: UMLS:C0022104 (irritable bowel syndrome)
 8,033 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

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.
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PMID:Reduction of wrap restraint stress-induced defecation by MKC-242, a novel benzodioxan derivative, via 5-HT1A-receptor agonist action in rats. 971 68

3-Amino-5,6,7,8-tetrahydro-2-{4-[4-(quinolin-2-yl)piperazin-1-yl]-butyl}quinazolin-4(3H)-one (TZB-30878), a novel 5-hydroxytryptamine (5-HT)(1A) agonist/5-HT(3) antagonist, is currently under development for the treatment of irritable bowel syndrome. The objective of this investigation was to obtain information on the biotransformation of TZB-30878. This compound has quinazoline, piperazine, and quinoline rings. Metabolites of [quinazoline-2-(14)C]TZB-30878 were determined using radio high-performance liquid chromatography on samples obtained after incubation with human hepatic microsomes. Eight metabolites were detected in the microsomal incubation mixture, and their structures were proposed by mass spectrometry techniques using TZB-30878 and two stable labeled TZB-30878 analogs, [quinoline-deuterium (D)(6)]TZB-30878 and [piperazin-D(8)]TZB-30878. Liquid chromatography/tandem mass spectrometry analyses suggested that the eight metabolites consisted of a cyclic metabolite (M6), four hydroxylated metabolites (M1, M2, M3, and M4) (three on quinoline ring and one on quinazoline ring), a deaminated metabolite (M5), and two metabolites (M7 and M8) that were presumably intermediates leading to the formation of the cyclic metabolite M6. Hydroxylation sites in the quinoline and quinazoline rings were predicted by electron density calculations and confirmed by comparison with authentic standards. To the best of our knowledge, N-deamination by microsomes leading to the formation of M5 appears to be novel. In addition, in vitro experiments in human liver microsomes with cytochrome P450 (P450)-specific inhibitors revealed that CYP3A4 was the major enzyme responsible for the metabolism of TZB-30878. Other P450 enzymes, such as a CYP2D6, played a minor role in its metabolism.
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PMID:Biotransformation of 3-amino-5,6,7,8-tetrahydro-2-{4-[4-(quinolin-2-yl)piperazin-1-yl]butyl}quinazolin-4(3H)-one (TZB-30878), a novel 5-hydroxytryptamine (5-HT)1A agonist/5-HT3 antagonist, in human hepatic cytochrome P450 enzymes. 1823 59

We have prepared a series of piperazinylpyridine derivatives for the treatment of irritable bowel syndrome (IBS). These compounds, which were designed by pharmacophore analysis, bind to both serotonin subtype 1A (5-HT1A) and subtype 3 (5-HT3) receptors. The nitrogen atom of the isoquinoline, a methoxy group and piperazine were essential to the pharmacophore for binding to these receptors. We also synthesized furo- and thienopyridine derivatives according to structure-activity relationship analyses. Compound 17c (TZB-20810) had high affinities to these receptors and exhibited 5-HT1A agonistic activity and 5-HT3 antagonistic activity concurrently, and is a promising drug for further development in the treatment of IBS.
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PMID:Design and synthesis of piperazinylpyridine derivatives as novel 5-HT1A agonists/5-HT3 antagonists for the treatment of irritable bowel syndrome (IBS). 1912 13