Gene/Protein Disease Symptom Drug Enzyme Compound
Pivot Concepts:   Target Concepts:
Query: UMLS:C0022104 (irritable bowel syndrome)
 8,033 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

The pharmacological properties of MA-2029, a novel motilin receptor antagonist, were investigated. In vitro, MA-2029 (1 to 30 nM) competitively inhibited motilin-induced contractions in isolated rabbit duodenal longitudinal muscle strips, with a pA2 value of 9.17+/-0.01 (n=5). However, contractile responses to acetylcholine and substance P were unaffected even at 1 microM of MA-2029. MA-2029 concentration-dependently inhibited the binding of [125 I]motilin to motilin receptors in a homogenate of rabbit colon smooth muscle tissue and membranes of HEK 293 cells expressing human motilin receptors. The pKi of MA-2029 was 8.58+/-0.04 in the rabbit colon homogenate (n=4) and 8.39 in the HEK 293 cells (mean of duplicate experiments). In vivo, orally-administered MA-2029 (3 to 30 mg/kg) dose-dependently inhibited colonic contractions induced by motilin (3 microg/kg, i.v.) in conscious rabbits. Inhibition was caused by all doses at 30 min after administration and by 10 mg/kg or more at 4 h after administration. The plasma concentration of MA-2029 correlated with its inhibitory effect. Furthermore, the oral administration of MA-2029 (0.3 to 3 mg/kg) also inhibited abdominal muscle contractions (an index of the visceral pain) induced by intravenous infusion of motilin (3 microg/kg/h) during colorectal distension in conscious rabbits. These results indicate that MA-2029 is an orally active, selective and competitive motilin receptor antagonist. It is suggested that this compound may be useful for gastrointestinal disorders associated with disturbed gastrointestinal motility such as irritable bowel syndrome.
 ...
PMID:Oral administration of MA-2029, a novel selective and competitive motilin receptor antagonist, inhibits motilin-induced intestinal contractions and visceral pain in rabbits. 1816 86

There is tremendous activity and excitement in the arena of drug development for the treatment of the irritable bowel syndrome (IBS). Pharmacologic therapy has been largely limited to gut acting therapeutic agents including antidiarrheals, laxatives and antispasmodics that primarily target individual symptoms. Various antidepressants have gained popularity although their efficacy in clinical trials has been modest and their clinical utility is limited by untoward side effects. Serotonergic agents have demonstrated efficacy on the global symptoms of IBS; however, recent concerns about safety have severely limited their use. Recent discoveries regarding the pathophysiology of IBS have revealed numerous potential therapeutic targets. Agents under development include newer serotonergic agents and antidepressants; chloride channel, guanylate cyclase, opioid and motilin receptor ligands; various central, peripheral and autonomic neural receptor ligands; and gut immune modulators.
 ...
PMID:Recent developments in the therapy of irritable bowel syndrome. 1823 48

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.
 ...
PMID:Development of drugs for gastrointestinal motor disorders: translating science to clinical need. 1825 67

The aim of this study was to assess the cardiovascular effect of MA-2029, a selective motilin receptor antagonist highly expected for the treatment of irritable bowel syndrome (IBS). MA-2029 inhibited the human ether-a-go-go-related gene (hERG) current at 100 microg/ml, but shortened action potential duration (APD) in isolated guinea pig papillary muscles at 10 and 100 microg/ml and the corrected QT (QTc) interval after oral administration of 30 and 300 mg/kg in conscious telemetered dogs. The discrepancy was probably caused by blockade of the Ca(2+) channel because MA-2029 inhibited the Ca(2+) current in isolated guinea pig myocytes. MA-2029 at 100 microg/ml also decreased the maximum rising velocity and action potential amplitude in the action potential study, indicating that MA-2029 has Na(+) channel blocking potential. In the cardiovascular study, MA-2029 at 30 mg/kg induced slight cardiovascular changes such as hypotension, QTc shortening, and PR prolongation possibly caused by Ca(2+) channel blockade. The plasma concentration at 4 hr after 30 mg/kg administration was 2.10 microg/ml, 200-fold higher than the effective concentration of MA-2029 as a motilin receptor antagonist. These results suggest that MA-2029 has sufficient cardiovascular safety although it inhibits multiple ion channels at supra-effective concentrations. On the other hand, cisapride, an effective IBS drug, showed clear hERG inhibition and APD prolongation at 100 ng/ml. Cisapride exhibited a narrow safety margin because it caused QT prolongation potential even at the therapeutic concentration. In conclusion, MA-2029 is a novel drug highly expected for the treatment of IBS with lower cardiovascular risk than cisapride.
 ...
PMID:Cardiovascular safety profile of MA-2029, a novel motilin receptor antagonist. 1904 84