The discovery of diazepinone-based 5-HT3 receptor partial agonists

Manning, David D.; Guo, Cheng; Zhang, Zhenjun; Ryan, Kristen; Naginskaya, Jennifer; Choo, Sok Hui; Masih, Liaqat; Earley, William G.; Wierschke, Jonathan D.; Brady, Catherine; Barnes, Nicholas M.; Guzzo, Peter R.

doi:10.1016/j.bmcl.2014.03.074

Cited by 6 publications

(1 citation statement)

References 12 publications

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“…Serotonin, despite being an important neurotransmitter in the CNS, is mostly (> 90%) present in enterochromaffin cells (ECs) in the GI tract ( 54 ). Release of serotonin in the intestine results in smooth muscle contraction or relaxation, GI transit time alternation and luminal secretion.…”

Section: Serotonergic Agonist/antagonistmentioning

confidence: 99%

Pharmacological Approach for Managing Pain in Irritable Bowel Syndrome: A Review Article

2017

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ContextVisceral pain is a leading symptom for patients with irritable bowel syndrome (IBS) that affects 10% - 20 % of the world population. Conventional pharmacological treatments to manage IBS-related visceral pain is unsatisfactory. Recently, medications have emerged to treat IBS patients by targeting the gastrointestinal (GI) tract and peripheral nerves to alleviate visceral pain while avoiding adverse effects on the central nervous system (CNS). Several investigational drugs for IBS also target the periphery with minimal CNS effects.Evidence of AcquisitionIn this paper, reputable internet databases from 1960 - 2016 were searched including Pubmed and ClinicalTrials.org, and 97 original articles analyzed. Search was performed based on the following keywords and combinations: irritable bowel syndrome, clinical trial, pain, visceral pain, narcotics, opioid, chloride channel, neuropathy, primary afferent, intestine, microbiota, gut barrier, inflammation, diarrhea, constipation, serotonin, visceral hypersensitivity, nociceptor, sensitization, hyperalgesia.ResultsCertain conventional pain managing drugs do not effectively improve IBS symptoms, including NSAIDs, acetaminophen, aspirin, and various narcotics. Anxiolytic and antidepressant drugs (Benzodiazepines, TCAs, SSRI and SNRI) can attenuate pain in IBS patients with relevant comorbidities. Clonidine, gabapentin and pregabalin can moderately improve IBS symptoms. Lubiprostone relieves constipation predominant IBS (IBS-C) while loperamide improves diarrhea predominant IBS (IBS-D). Alosetron, granisetron and ondansetron can generally treat pain in IBS-D patients, of which alosetron needs to be used with caution due to cardiovascular toxicity. The optimal drugs for managing pain in IBS-D and IBS-C appear to be eluxadoline and linaclotide, respectively, both of which target peripheral GI tract.ConclusionsConventional pain managing drugs are in general not suitable for treating IBS pain. Medications that target the GI tract and peripheral nerves have better therapeutic profiles by limiting adverse CNS effects.

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Section: Serotonergic Agonist/antagonistmentioning

confidence: 99%