Pharmacological profile of YM-31636, a novel 5-HT3 receptor agonist, in vitro

Ito, Hiroyuki; Kiso, Tetsuo; Miyata, Keiji; Kamato, Takeshi; Yuki, Hidenobu; Akuzawa, Shinobu; Nagakura, Yukinori; Yamano, Michiyo; Suzuki, Mami; Naitoh, Yuki; Sakai, Hideto; Iwaoka, Kiyoshi; Yamaguchi, Tokio

doi:10.1016/s0014-2999(00)00851-7

Cited by 18 publications

(8 citation statements)

References 35 publications

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“…The introduction of a quinazoline ring and multiple chloro groups to the aromatic ring has been shown to increase the lipophilicity of both these compounds, demonstrating how the construction of brain-penetrable analogs might be achieved in future [62]. N-methylquipazine (NMQ) has also been extensively manipulated by fusing aromatic or heteroaromatic rings at various positions, which has resulted in a series of compounds with varied affinities [63][64][65][66][67][68][69]. The design of novel compounds has enabled the development of pharmacophore models.…”

Section: -Ht 3 Receptor Agonistsmentioning

confidence: 99%

5-HT3 Receptors

Thompson

Lummis

2006

CPD

205

173

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The 5-HT(3) receptor is a member of the Cys-loop family of ligand-gated ion channels. These receptors are located in both the peripheral and central nervous systems, where functional receptors are constructed from five subunits. These subunits may be the same (homopentameric 5-HT(3A) receptors) or different (heteropentameric receptors, usually comprising of 5-HT(3A) and 5-HT(3B) receptor subunits), with the latter having a number of distinct properties. The 5-HT(3) receptor binding site is comprised of six loops from two adjacent subunits, and critical ligand binding amino acids in these loops have been largely identified. There are a range of selective agonists and antagonists for these receptors and the pharmacophore is reasonably well understood. There are also a wide range of compounds that can modulate receptor activity. Studies have suggested many diverse potential disease targets that might be amenable to alleviation by 5-HT(3) receptor selective compounds but to date only two applications have been fully realised in the clinic: the treatment of emesis and irritable-bowel syndrome.

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Section: -Ht 3 Receptor Agonistsmentioning

confidence: 99%

5-HT3 Receptors

Thompson

Lummis

2006

CPD

205

173

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“…-Hytroxytryptamine (5-HT; serotonin), an important biogenic amine is widely distributed throughout the body. 1 It has been estimated that approximately 60-90% (up to 10 mg in humans) of mammalian 5-HT stores are found in the gastrointestinal (GI) tract and most 5-HT exists in enterochromaffin (EC) cells. 2 5-Hydroxytryptamine is secreted from EC cells in response to a variety of luminal mechanical and chemical stimuli.…”

Section: Introductionmentioning

confidence: 99%

Regulation of Ion Transport by 5‐hydroxytryptamine in Rat Colon

Yang

Zhu

Chan

2004

Clin Exp Pharma Physio

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1. 5-Hydroxytryptamine (5-HT) modulates the motility and secretion of the gastrointestinal tract. To examine the direct effect of 5-HT on the secretions of colonic epithelial cells, a short-circuit current was used to measure electrolyte transport in the rat stripped distal colon. A neuronal Na+ channel blocker and a cyclo-oxygenase inhibitor were routinely added in experiments to abolish the effects of the enteric nervous system and endogenous prostaglandin, respectively. 2. Basolateral application of 5-HT (10 micromol/L) induced an increase in the short circuit current (ISC). Removal of extracellular Cl-, HCO3- or both resulted in a 59.6, 76.4 and 90% reduction of 5-HT-elicited responses, respectively. The Ca(2+)-dependent Cl- channel blocker 4,4'-diisothiocyanatostilbene-2,2'-disulphonic acid (DIDS) had no effect on the 5-HT-induced increase in ISC, but the selective cystic fibrosis transmembrane conductance regulator (CFTR) channel blocker glibenclamide (1 mmol/L) inhibited 5-HT-induced increases in ISC by approximately 92.9%. Removal of apical Na+ reduced the 5-HT-induced increase in ISC by 33.3%. 3. Basolateral pretreatment with 100 micromol/L bumetanide (an inhibitor of the Na(+)-K(+)-2Cl- cotransporter), 200 micromol/L DIDS (an inhibitor of the Na(+)-HCO3- transporter or the Cl-/HCO3- exchanger) or both decreased the DeltaISC induced by 5-HT by approximately 75.5, 59.0 and 86.3%, respectively. Removal of basolateral Na+ also reduced the current evoked by 5-HT. 4. The selective 5-HT4 antagonist GR113808 (1 micromol/L) totally abolished the 5-HT-induced increase in ISC, whereas 2-methyl-5-HT (100 micromol/L) induced a weak ISC response. 5. In conclusion, the present study has demonstrated that 5-HT can elicit Cl(-)- and HCO3- anion secretion and Na+ absorption by acting directly on colonic epithelial cells via 5-HT4 receptors.

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“…Such a difference could not be explained by regional differences in receptor density, because another 5‐HT 3 receptor agonist, YM‐31363, led to an inverse result. YM‐31363 behaves as a full agonist in the mechanical response, whereas it showed partial agonistic activity in ion secretion in the guinea‐pig colon 37 . Alternatively, the heterogeneity of 5‐HT 3 receptors may account for the regional difference in intrinsic efficacy.…”

Section: Discussionmentioning

confidence: 99%

Comparison between partial agonist (ME3412) and antagonist (alosetron) of 5‐hydroxytryptamine 3 receptor on gastrointestinal function

Kawano

Mori

et al. 2005

Neurogastroenterology Motil

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Therapeutic use of 5-hydroxytryptamine 3 (5-HT(3)) receptor antagonists for diarrhoea-predominant irritable bowel syndrome may be accompanied by constipation. We hypothesized that ME3412, 5-chloro-2-(1,4-diazacycloheptan-1-yl)-7-methylbenzoxazole, a novel partial agonist of the 5-HT(3) receptor, would minimize constipation without reducing antidiarrhoeal activity. Receptor binding studies showed that ME3412 is highly selective for the human 5-HT(3) receptor (K(i) = 1.51 nmol L(-1)). A 5-HT(3) receptor agonist, 2-methyl-5-HT, caused contractile response in the isolated guinea-pig ileum and accelerated secretion in the guinea-pig colonic mucosal preparation. ME3412 and 5-HT(3) receptor antagonist, alosetron, antagonized the 2-methyl-5-HT-induced responses with similar potency in insurmountable and surmountable manner, respectively. ME3412 caused weak agonism in isolated ileum strips and also in the colonic mucosa with intrinsic activity of 0.09 and 0.59, respectively. In conscious dogs, alosetron (3 microg kg(-1) i.v.) suppressed the migrating motor complex (MMC), whereas a relatively high dose (300 microg kg(-1)) of ME3412 was required for inhibition of MMC. ME3412 and alosetron suppressed 5-HT induced-diarrhoea in mice. In contrast, ME3412 did not significantly affect colonic propulsion compared with alosetron. These results imply that the partial agonist may relieve diarrhoea with low risk of inducing constipation.

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Pharmacological profile of YM-31636, a novel 5-HT3 receptor agonist, in vitro

Cited by 18 publications

References 35 publications

5-HT3 Receptors

5-HT3 Receptors

Regulation of Ion Transport by 5‐hydroxytryptamine in Rat Colon

Comparison between partial agonist (ME3412) and antagonist (alosetron) of 5‐hydroxytryptamine 3 receptor on gastrointestinal function

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