Design and Synthesis of Piperazinylpyridine Derivatives as Novel 5-HT1A Agonists/5-HT3 Antagonists for the Treatment of Irritable Bowel Syndrome (IBS)

Asagarasu, Akira; Matsui, Teruaki; Hayashi, Hiroyuki; Tamaoki, Satoru; Yamauchi, Yukinao; Sato, Michitaka

doi:10.1248/cpb.57.34

Cited by 21 publications

(21 citation statements)

References 15 publications

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“…Recently, novel mixed 5-HT1A agonists/5-HT3 antagonists, 5-HT1B/D agonists, and 5-HT2B antagonists have been proposed as new therapeutics for IBS (Tack et al, 2000; Mulak and Paradowski, 2006; Vera-Portocarrero et al, 2008; Asagarasu et al, 2009; O’Mahony et al, 2010b). …”

Section: Past Present and Future Of Anti-ibs Drugs Targeting The Brmentioning

confidence: 99%

Brain-Gut Interactions in IBS

Fichna¹,

Storr²

2012

Front. Pharmacol.

110

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Irritable bowel syndrome (IBS) is a common gastrointestinal disorder with an estimated prevalence of 10–20%. Current understanding of the pathophysiology of IBS is incomplete due to the lack of a clearly identified pathological abnormality and due to the lack of reliable biomarkers. Possible mechanisms believed to contribute to IBS development and IBS like symptoms include physical stressors, such as infection or inflammation, psychological, and environmental factors, like anxiety, depression, and significant negative life events. Some of these mechanisms may involve the brain-gut axis (BGA). In this article we review the current knowledge on the possible involvement of the BGA in IBS and discuss new directions for potential future therapies of IBS.

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Section: Past Present and Future Of Anti-ibs Drugs Targeting The Brmentioning

confidence: 99%

Brain-Gut Interactions in IBS

Fichna¹,

Storr²

2012

Front. Pharmacol.

110

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“…However, the clinical development of AZD7371 has been discontinued due to severe adverse events including hallucinations, and the inability to demonstrate significant efficacy in IBS patients compared with placebo (Drossman et al, 2008). Recently, a new piperazinylpyridine derivative, TZB-20810 with mixed 5-HT 1A agonistic and 5-HT 3 antagonistic activities has been proposed as a promising drug in the treatment of IBS (Asagarasu et al, 2009). …”

Section: Introductionmentioning

confidence: 99%

Stress and visceral pain: From animal models to clinical therapies

Larauche

Mulak

Taché

2012

Experimental Neurology

180

207

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Epidemiological studies have implicated stress (psychosocial and physical) as a trigger of first onset or exacerbation of irritable bowel syndrome (IBS) symptoms of which visceral pain is an integrant landmark. A number of experimental acute or chronic exteroceptive or interoceptive stressors induce visceral hyperalgesia in rodents although recent evidence also points to stress-related visceral analgesia as established in the somatic pain field. Underlying mechanisms of stress-related visceral hypersensitivity may involve a combination of sensitization of primary afferents, central sensitization in response to input from the viscera and dysregulation of descending pathways that modulate spinal nociceptive transmission or analgesic response. Biochemical coding of stress involves the recruitment of corticotropin releasing factor (CRF) signaling pathways. Experimental studies established that activation of brain and peripheral CRF receptor subtype 1 plays a primary role in the development of stress-related delayed visceral hyperalgesia while subtype 2 activation induces analgesic response. In line with stress pathways playing a role in IBS, non-pharmacologic and pharmacologic treatment modalities aimed at reducing stress perception using a broad range of evidence-based mind-body interventions and centrally-targeted medications to reduce anxiety impact on brain patterns activated by visceral stimuli and dampen visceral pain.

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“…18 During the last two decades, this pharmacophore has been continuously refined. 19−25 The consensus is that 5-HT 3 receptor ligands share three pharmacophore features: an aromatic part (A), a basic moiety (B) and an intervening hydrogen bond acceptor (C) moiety (Figure 1b). Interestingly, Jørgensen and co-workers recently published 5-HT 3 A receptor ligands that lack a positively charged basic moiety, and it is suggested that these compounds exert their effects via an allosteric site of the receptor.…”

Section: Introductionmentioning

confidence: 99%

Design, Synthesis, and Structure–Activity Relationships of Highly Potent 5-HT₃ Receptor Ligands

Verheij¹,

Thompson

Muijlwijk‐Koezen³

et al. 2012

J. Med. Chem.

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The 5-HT3 receptor, a pentameric ligand-gated ion channel (pLGIC), is an important therapeutic target. During a recent fragment screen, 6-chloro-N-methyl-2-(4-methyl-1,4-diazepan-1-yl)quinazolin-4-amine (1) was identified as a 5-HT3R hit fragment. Here we describe the synthesis and structure–activity relationships (SAR) of a series of (iso)quinoline and quinazoline compounds that were synthesized and screened for 5-HT3R affinity using a [3H]granisetron displacement assay. These studies resulted in the discovery of several high affinity ligands of which compound 22 showed the highest affinity (pKi > 10) for the 5-HT3 receptor. The observed SAR is in agreement with established pharmacophore models for 5-HT3 ligands and is used for ligand–receptor binding mode prediction using homology modeling and in silico docking approaches.

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Design and Synthesis of Piperazinylpyridine Derivatives as Novel 5-HT1A Agonists/5-HT3 Antagonists for the Treatment of Irritable Bowel Syndrome (IBS)

Cited by 21 publications

References 15 publications

Brain-Gut Interactions in IBS

Brain-Gut Interactions in IBS

Stress and visceral pain: From animal models to clinical therapies

Design, Synthesis, and Structure–Activity Relationships of Highly Potent 5-HT₃ Receptor Ligands

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Design and Synthesis of Piperazinylpyridine Derivatives as Novel 5-HT1A Agonists/5-HT3 Antagonists for the Treatment of Irritable Bowel Syndrome (IBS)

Cited by 21 publications

References 15 publications

Brain-Gut Interactions in IBS

Brain-Gut Interactions in IBS

Stress and visceral pain: From animal models to clinical therapies

Design, Synthesis, and Structure–Activity Relationships of Highly Potent 5-HT3 Receptor Ligands

Contact Info

Product

Resources

About

Design, Synthesis, and Structure–Activity Relationships of Highly Potent 5-HT₃ Receptor Ligands