VIEWPOINT Development of drugs for gastrointestinal motor disorders: translating science to clinical need G. J. SANGER* & D. H. ALPERS  *Immuno-Inflammatory CEDD, GlaxoSmithKline, Stevenage, Hertfordshire, UK  Washington University School of Medicine, Deptartment of Internal Medicine, St Louis, MO, USA 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 recep- tors or b 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and the long-established 5-HT 4 agonist and D 2 antagonist metoclopramide; tegaserod, a non-selective ligand, was withdrawn.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 pharmacody- namic 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 irrita- ble 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. Keywords 5-hydroxytryptamine, constipation, dysp- epsia, irritable bowel syndrome, lubiprostone, motilin. INTRODUCTION Drugs which are prescribed to increase gastrointesti- nal (GI) motility include the non-selective 5-hydroxy- tryptamine (5-HT) 5-HT 4 receptor agonist and dopamine D 2 receptor antagonist metoclopramide, the peripherally-restricted D 2 receptor antagonist dom- peridone (not in the USA) and as an off-label use, the antibiotic and motilin receptor agonist erythromycin. Most recently, the chloride channel activator lubipro- stone, which increases fluid secretion into the intes- tinal lumen and secondarily stimulates peristalsis because of increased intraluminal content, has been registered for the treatment of constipation. The non- selective 5-HT 4 receptor agonist tegaserod (also active at 5-HT 1B/1D and 5-HT 2A , 2B receptors) was withdrawn from the USA market (tegaserod never achieved registration in Europe) because of safety fears. Drugs used to reduce GI motility include several, which are sold Ôover the counterÕ (such as the partial opiate receptor agonist, loperamide) or which were developed many years ago (such as the calcium channel blocker mebeverine). The only recent introduction of a drug known to reduce colonic motility is the 5-HT 3 recep- tor antagonist alosetron, prescribed for the treatment Address for Correspondence Gareth J Sanger, Immuno-Inflammatory CEDD, Glaxo- SmithKline, Gunnels Wood Road, Stevenage, Hertfordshire, SG1 2NY, UK. Tel: (0)1438 763191; e-mail: Gareth_J_Sanger@gsk.com Received: 27 November 2007 Accepted for publication: 21 December 2007 Neurogastroenterol Motil (2008) 20, 177–184 doi: 10.1111/j.1365-2982.2008.01084.x Ó 2008 The Authors Journal compilation Ó 2008 Blackwell Publishing Ltd 177