Development of drugs for gastrointestinal motor disorders: translating science to clinical need

Abstract

Only a small number of new drugs have recently become available for gastrointestinal (GI) disorders. This is partly because we await outcomes of research into functional bowel disorder aetiology (e.g., role of microbiota) and of trials to control stress- related or painful GI symptoms (e.g., via CRF(1) receptors or beta(3) adrenoceptors). Nevertheless, only the ClC-2 channel activator lubiprostone has recently reached the clinic, joining the 5-HT(3) antagonist alosetron and the long-established 5-HT(4) agonist and D(2) antagonist metoclopramide; tegaserod, a non-selective ligand, was withdrawn. Interestingly, each has shortcomings, providing opportunities for molecules with 5-HT(4) or motilin receptor selectivity, and for new biology via guanylate cyclase C or ghrelin receptor activation. For translation into new drugs, the molecule must have appropriate efficacy, selectivity and pharmacodynamic properties. It is argued that the compound must then be evaluated in conditions where changes in motility are known to exist, before considering more difficult symptomatic conditions such as irritable bowel syndrome (IBS) or functional dyspepsia (FD), where relationships with disordered motility are unclear. Thus, it may be better to begin studying a gastric prokinetic in diabetics requiring improved glucose control, rather than in FD. Notably, new 5-HT(4) receptor agonists are being evaluated firstly as treatments of constipation, not IBS. New antidiarrhoeal agents should be developed similarly. Thus, progression of new drugs may require initial studies in smaller patient populations where clinical outcome is better defined. Only then can disease-related ideas be properly tested and drugs brought forward for these disorders (with high clinical need) and then, if successful for IBS and FD.

Enhanced Gastrointestinal Motility with Orally Active Ghrelin Receptor Agonists

“…The utility of GhrR agonism in a variety of models of GI pathology has been reported recently (Peeters, 2006;Sanger, 2008;Sanger and Alpers, 2008). Treatment with ghrelin has been shown to successfully ameliorate diabetic gastroparesis in both animal models of the disease (Qiu et al, 2008a) and in humans (Murray et al, 2005).…”

“…Despite 50% structural homology between ghrelin and the prokinetic peptide hormone motilin, the activity of these two hormones has been shown convincingly to function via distinct receptors (Depoortere et al, 2003;Sanger, 2008). The ability to stimulate hunger, FI, and GI motility suggests that ghrelin agonists may represent an attractive and unique therapeutic strategy for the treatment of motility disorders (Sanger and Alpers, 2008), such as diabetic and idiopathic gastroparesis, postoperative ileus, opiate-induced bowel dysfunction, and chronic constipation of idiopathic origin (Murray et al, 2005;Tack et al, 2005;Levin et al, 2006;Qiu et al, 2008b,c).…”

The Physiology, Signaling, and Pharmacology of Dopamine Receptors

“…Several D2 dopamine receptor antagonists, such as bromopride, domperidone, droperidol, metoclopramide, prochlorperazine, thiethylperazine, and triflupromazine, have found clinical application as antiemetic drugs in the treatment of nausea and vomiting (Axelrod, 1997). Metoclopramide and bromopride are also used clinically as prokinetic drugs for the gastrointestinal tract to increase muscle contractions in the upper digestive tract (Sanger and Alpers, 2008). The list of dopamine receptor agonists and antagonists that have been used clinically is presented in Table 3.…”

Enterclysis versus enterography: the unsettled issue

“…This can be easily done by motility enhancing substances, including metoclopramide [10]. Thus, it is not surprising that small bowel distension for MREg was inferior to MREc.…”