GI motility: nootropics and compounds | sci-wiki

Metoclopramide

Metoclopramide is a medication that relieves nausea and vomiting and stimulates the movement of the upper digestive tract. Belonging to the benzamide class and acting mainly as a dopamine D2 receptor blocker, it is used for conditions such as chemotherapy-induced and post-surgical nausea, gastroparesis, and gastroesophageal reflux, and it is sold under brand names including Reglan and Maxolon. Because it can cause movement-related side effects with prolonged use, treatment courses are usually kept short, and it appears on the World Health Organization's list of essential medicines.

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Gastrointestinal

Mosapride

Mosapride is a gastroprokinetic drug that acts as a selective agonist of the serotonin 5-HT4 receptor, used to improve the movement of the upper digestive tract. It is prescribed for conditions such as chronic gastritis, gastroesophageal reflux disease and functional dyspepsia, where sluggish stomach emptying contributes to symptoms. Marketed largely in Japan and other parts of Asia, it is noted for a favorable cardiac safety profile compared with the older prokinetic cisapride.

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Blend

Rabeprazole + Domperidone

Rabeprazole plus domperidone is a fixed-dose combination medicine that pairs two drugs acting on the upper digestive tract: rabeprazole, a proton pump inhibitor that suppresses stomach acid, and domperidone, a prokinetic and antiemetic that speeds the movement of food out of the stomach. The combination is used mainly for acid reflux and related conditions accompanied by nausea, bloating, or slow gastric emptying. It is marketed in India and various other countries, often as a single capsule, but it is not approved in the United States, where domperidone itself is unlicensed.

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Gastrointestinal

Cisapride

Cisapride is a substituted benzamide 5-HT4 receptor agonist that was one of the most widely used gastrointestinal prokinetic agents of the 1990s, marketed as Propulsid and Prepulsid for gastroesophageal reflux, gastroparesis, and other dysmotility disorders. It accelerates gastric emptying and gut transit by enhancing acetylcholine release from the myenteric plexus. Its clinical career ended after it was found to block the hERG cardiac potassium channel and prolong the QT interval, causing torsades de pointes and sudden death, leading to near-worldwide withdrawal around 2000. Cisapride is the definitive cautionary tale that reshaped 5-HT4 agonist development.

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Gastrointestinal

Minesapride

Minesapride is a benzamide 5-HT4 receptor partial agonist with high receptor affinity, developed by Sumitomo Dainippon Pharma as a gastrointestinal prokinetic for constipation-predominant irritable bowel syndrome. In a phase 2 trial in Japan it increased complete spontaneous bowel movements and reduced abdominal and overall irritable bowel severity, with diarrhea the most common adverse event. A dedicated thorough QT study found no effect on cardiac QT interval at therapeutic or supratherapeutic doses, addressing the historical cardiac concern for the class. Minesapride is investigational and not approved.

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Gastrointestinal

Naronapride

Naronapride is a highly selective 5-HT4 receptor agonist developed as a benzamide prokinetic intended to replicate the efficacy of cisapride without its cardiac liabilities, notably without QT prolongation and without cytochrome P450-dependent metabolism. It accelerates gastric emptying and colonic transit and has been studied for chronic constipation, gastroparesis, and broader gastrointestinal dysmotility. In healthy volunteers it produced dose-dependent acceleration of colonic transit and looser stools with no identified safety issues. Naronapride is investigational and not approved for clinical use.

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Gastrointestinal

Renzapride

Renzapride is a bicyclic benzamide that acts as a full 5-HT4 receptor agonist and simultaneously as a 5-HT3 receptor antagonist, a dual mechanism that made it an unusual candidate for irritable bowel syndrome. It accelerates gastrointestinal transit through 5-HT4 agonism while its 5-HT3 antagonism was intended to modulate visceral sensitivity, and it was developed principally for constipation-predominant irritable bowel syndrome. Radioligand studies confirm high affinity for 5-HT3 and 5-HT4 receptors, with only minor metabolites and little cytochrome P450 inhibition. Renzapride reached late-stage trials but was not approved.

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Peptide

Spexin

Spexin, also called neuropeptide Q, is a small 14-amino-acid peptide discovered by bioinformatics and later shown to be an endogenous ligand of galanin receptors 2 and 3, part of a shared spexin, galanin, and kisspeptin family. It is broadly expressed across endocrine and nervous tissue and functions as a regulatory adipokine, with circulating levels reduced in obesity and linked to metabolic and inflammatory markers. Spexin also stimulates gastrointestinal motility through galanin receptor 2 and has been associated with appetite, cardiovascular, reproductive, and mood-related functions. It is an endogenous peptide of growing translational interest.

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Gastrointestinal

TD-8954

TD-8954 is a potent, selective 5-HT4 receptor agonist built on a novel 2-alkylbenzimidazole scaffold and developed by Theravance as a clinical-stage gastrointestinal prokinetic. It has subnanomolar 5-HT4 binding affinity and demonstrated prokinetic activity across multiple animal species, and it was advanced into clinical evaluation for gastrointestinal motility disorders including postoperative ileus and chronic constipation. Dedicated cardiovascular studies found no significant off-target effects on coronary tone, platelet aggregation, or the hERG cardiac potassium channel. TD-8954 is investigational and not approved.

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Gastrointestinal

Tegaserod

Tegaserod is an aminoguanidine indole 5-HT4 receptor partial agonist that was the first serotonergic prokinetic approved specifically for constipation-predominant irritable bowel syndrome and chronic idiopathic constipation, marketed as Zelnorm and Zelmac. It stimulates gut motility and secretion and modestly improves global symptoms and bowel frequency in affected patients, predominantly women. It was withdrawn in 2007 over an apparent excess of cardiovascular ischemic events, then later reintroduced in the United States for a restricted population. Tegaserod is a historically pivotal but only partially selective 5-HT4 agonist.

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Gastrointestinal

Velusetrag

Velusetrag is a highly selective, high-affinity 5-HT4 receptor agonist with pan-gastrointestinal prokinetic activity, developed by Theravance as a next-generation successor to cisapride that avoids off-target cardiac effects. It accelerates gastric emptying and colonic transit and has been evaluated in chronic constipation and, most extensively, in diabetic and idiopathic gastroparesis. In a phase 2b gastroparesis trial it normalized gastric emptying in most patients at the highest dose, though symptomatic benefit was seen mainly at the lowest 5 mg dose. Velusetrag is investigational and has not received marketing approval.

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