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)

In this chapter it is described how, starting from different approaches and through extensive medicinal chemistry studies, several discovery compounds were optimized and reached the development stage. The first tachykinin receptor antagonist to reach the market in 2003 for chemotherapy-induced emesis has been aprepitant. Other clinical candidates (for central nervous system disorders: osanetant, talnetant and saredutant; for irritable bowel syndrome: nepadutant and saredutant) are in advanced clinical phase. The clinical studies reported in the literature and the destiny of the clinical candidates, where available, will be reviewed.
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PMID:Tachykinin receptors antagonists: from research to clinic. 1691 26

Mast cells are involved in allergic reactions, where they secrete numerous vasoactive, inflammatory and nociceptive mediators in response to immunoglobulin E (IgE) and antigen. However, they have also been implicated in inflammatory conditions, such as painful bladder syndrome/interstitial cystitis (PBS/IC), irritable bowel syndrome (IBS) and migraines, all of which occur more often in women and are exacerbated during ovulation, but are suppressed during pregnancy. Mast cells express high affinity estrogen receptors and estradiol augments their secretion, while tamoxifen inhibits it. Here we report that progesterone (100 nM), but not the structurally related cholesterol, inhibits histamine secretion from purified rat peritoneal mast cells stimulated immunologically or by substance P (SP), an effect also documented by electron microscopy. These results suggest that mast cell secretion may be regulated by progesterone and may explain the reduced symptoms of certain inflammatory conditions during pregnancy.
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PMID:Progesterone inhibits mast cell secretion. 1716

The 5-HT3 receptor is a pentameric ligand-gated cation channel which is found in the central and peripheral nervous system and on extraneuronal locations like lymphocytes, monocytes and fetal tissue. Five monomer subtypes, the 5-HT(3A-E) subunits, have been identified which show differences in the amino-terminal and the transmembrane region. The functional relevance of different receptor compositions is not yet clarified. 5-HT3 receptors are located predominantly in CNS regions that are involved in the integration of the vomiting reflex, pain processing, the reward system and anxiety control. The preferential localization on nerve endings is consistent with a physiological role of 5-HT3 receptors in the control of neurotransmitter release such as dopamine, cholecystokinin, glutamate, acetylcholine, GABA, substance P, or serotonin itself. 5-HT3-receptor agonists cause unpleasant effects like nausea and anxiety, and no clinical use has been considered. In contrast, the introduction of 5-HT3-receptor antagonists for chemotherapy-induced vomiting was extremely successful. After development of other gastrointestinal indications like postoperative vomiting and diarrhea-predominant irritable bowel syndrome recent research focuses on rheumatological indications such as fibromyalgia, rheumatoid arthritis and tendinopathies. Positive effects have also been observed for pain syndromes such as chronic neuropathic pain and migraine. These effects seem to be related to substance P-mediated inflammation and hyperalgesia. Furthermore, antiinflammatory and immunomodulatory properties have been observed for 5-HT3-receptor antagonists which might explain promising findings in systemic sclerosis and other immunological conditions. For all of these innovative indications the optimal dosing schedule is a crucial issue, since a bell-shaped dose-response curve has been observed repeatedly for 5-HT3-receptor antagonists, particularly in CNS effects.
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PMID:The neuronal 5-HT3 receptor network after 20 years of research--evolving concepts in management of pain and inflammation. 1731 6

There is a large unmet need for effective drugs for the treatment of gastrointestinal disorders, notably irritable bowel syndrome, functional dyspepsia and gastroesophageal reflux disease. The market value for an effective irritable bowel syndrome therapeutic agent is estimated at over US10 billion dollars per annum. Each of these disorders seems to have a neural component, involving the intrinsic innervation of the gastrointestinal system, its extrinsic innervation or both. The substantially improved understanding of the transmitters, receptors and ion channels of enteric neurons that now exists has led to targeted therapy. The most promising targets so far have been 5-hydroxytryptamine receptors. Other targets include opioid, cholecystokinin, tachykinin, cannabinoid, corticotropin-releasing factor and protease-activated receptors. Ion channels are also potential targets. Although current knowledge has yet to be adequately translated into effective therapies, each of the targets holds promise for the future that might be realized as new compounds with appropriate receptor specificity and pharmacodynamic profiles are developed.
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PMID:Novel therapeutic targets for enteric nervous system disorders. 1776 56

The efficacy of electroacupuncture (EA) for treating patients with diarrhea-predominant IBS has been confirmed in the authors' former research, but the regulatory mechanism of EA in IBS is still unknown. The aim of this study was to explore the relationship between the effect of EA on treating IBS rats and the activation and proliferation of mast cell (MC), the secretion of substance P(SP), and vasoactive intestinal polypeptide (VIP). The IBS rat model was set up with stress of binding limbs and colorectal distention. All rats were randomly assigned to four groups (Normal, Model, Tegaserod and EA). Hematoxylin and eosin staining has been used to observe the pathological change in the rats' colonic mucosa and an AWR scoring system has been applied to evaluate improvement of visceral hypersensitivity in various methods of the different groups. Toluidine blue improved method (TBI) and immunohistochemistry have also been involved in observations of mucous mast cells in the colon, change of c-fos positive cells, and secretion of SP, SPR, VIP, VIPR in the local colon. Firstly, the threshold of visceral sensitivity in the rats model with IBS was remarkably reduced (P < 0.01). The MC count in colonic mucosa and c-fos positive cells count increased significantly (P < 0.01) with positive correlation within each. Secondly, EA on ST-25 and Tegaserod pouring into the stomach can inhibit the proliferation and activation of MC in the colon and regulate secretion of SP, SPR, VIP, VIPR (P < 0.01, P < 0.05), while the effect of EA is obviously superior to Tegaserod. We concluded, firstly, that the abnormal proliferation and activation of mucous mast cells in the colon, and oversecretion of neuropeptides such as SP, VIP and their receptors could be one of key mechanisms of etiology of IBS. Secondly, the inhibition of activation and proliferation and the secretion of SP, VIP could be major effects of EA when treating rats with IBS.
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PMID:Regulatory mechanism of electroacupuncture in irritable bowel syndrome: preventing MC activation and decreasing SP VIP secretion. 1799 87

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.
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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

The NK(2) receptor belongs to the family of tachykinin neurotransmitters. It has been reported to be involved in several pathological conditions, and selective antagonists are potentially useful drugs for the treatment of asthma, irritable bowel syndrome, cystitis, and depression. Starting from in-house capped dipeptide libraries, we were able to identify a number of molecules with sub-nanomolar binding affinity for the hNK(2) receptor. All were characterized by a rigid core structure with a strong constraint induced by an alpha,alpha-cyclopentaneglycine fragment. Herein we report the further elaboration of three initial basic structures. The planar benzothiophene group was substituted with a series of biphenyl and heterobiphenyl moieties that are well tolerated in terms of receptor affinity. The new compounds also maintained good antagonist potency in an in vitro functional assay, and a number of them showed significant in vivo activity after intravenous administration in our guinea pig model.
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PMID:alpha,alpha-Cyclopentaneglycine dipeptides capped with biaryls as tachykinin NK(2) receptor antagonists. 1839 14

The diagnosis and treatment of irritable bowel syndrome (IBS) are complicated. Artichoke extracts are well known to be helpful in various gastrointestinal disorders. A hydrophilic extract 36_U mainly containing luteolin-7-glycoside, luteolin-7-O-glucoside, small amounts of cynarin and luteolin increased contraction of rat ileum. This is mainly mediated by 5-HT(3) - and 5-HT(2) receptors but not 5-HT(4) receptors as can be derived by using specific antagonists such as tropisetrone, GR113806 and ketanserine. Additional mechanisms (receptors) are involved since the combination of these three antagonists was not able to fully prevent the contractive effect of extract 36_U. The lipophilic extract 36_EB mainly containing cynarin, luteolin including its glycosides, and cholorogenic acid in contrast to extract 36_U had a relaxing effect which could hardly be washed out. It was diminishing a serotonin effect and was not modified by ACh or substance P. The peristaltic threshold, i.e. the distension necessary for inducing a pathophysiologically relevant propulsion activity, is one of the important features being correlated with IBS. The peristaltic threshold was decreased by both serotonin and extract U_36. From the data it can be derived that the extract 36_U may be useful in IBS combined with obstipation when gastrointestinal contraction is necessary, whereas 36_EB may be useful in IBS combined with diarrhea when gastrointestinal relaxation is desired. Especially interesting are the influence on the threshold. It would be interesting to know which effects are mediated via cynarin and luteolin or its glycosides.
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PMID:Effect of two artichoke extracts (36_U and 36_EB) on rat ileum (with respect to bowel syndrome) and the peristaltic threshold. 1842 4

In women, clinical studies suggest that pain syndromes such as irritable bowel syndrome and interstitial cystitis, which are associated with visceral hyperalgesia, are often comorbid with endometriosis and chronic pelvic pain. One of the possible explanations for this phenomenon is viscerovisceral cross-sensitization, in which increased nociceptive input from an inflamed pelvic organ sensitizes neurons that receive convergent input to the same dorsal root ganglion (DRG) from an unaffected visceral organ. Nociception induces up-regulation of cellular mechanisms such as phosphorylated extracellular signal-regulated kinase (pERK) and substance P (SP), neurotransmitters associated with induced pain sensation. The purpose of this study was to determine, in a rodent model, whether uterine inflammation increased the number of pERK- and SP-positive neurons that received input from both the uterus and the colon. Cell bodies of colonic and uterine DRG were retrogradely labeled with fluorescent tracer dyes microinjected into the colon/rectum and into the uterus. Ganglia were harvested for fluorescent microscopy to identify positively stained neurons. Approximately 6% of neurons were colon specific and 10% uterus specific. Among these uterus- or colon-specific neurons, up to 3-5% of DRG neurons in the lumbosacral neurons (L1-S3 levels) received input from both visceral organs. Uterine inflammation increased the number of pERK- and SP-immunoreactive DRG neurons innervating specifically colon, or innervating specifically uterus, and those innervating both organs. These results suggest that a localized inflammation activates primary visceral afferents, regardless of whether they innervate the affected organ. This visceral sensory integration in the DRG may underlie the observed comorbidity of female pelvic pain syndromes.
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PMID:Inflammation in the uterus induces phosphorylated extracellular signal-regulated kinase and substance P immunoreactivity in dorsal root ganglia neurons innervating both uterus and colon in rats. 1847 47

Tachykinin NK(2) receptor antagonists are potentially beneficial in treating various disorders including irritable bowel syndrome, urinary incontinence, depression and anxiety. The current study evaluates the frequency of single nucleotide polymorphisms (SNPs) in the human NK(2) receptor gene (TACR2). In addition, the potency of the endogenous peptide agonist neurokinin A (NKA), and the small molecule antagonists saredutant (NK(2)-selective) and ZD6021 (pan-NK antagonist) at the various NK(2) receptor protein variants were determined. The TACR2 gene was sequenced from 37 individuals. Two amino acid changing SNPs encoding the NK(2) receptor variants Ile23Thr and Arg375His were found. The frequency of the four possible protein variants differed between populations. Site-directed mutagenesis was performed introducing either SNP or both SNPs into the TACR2 gene and the constructs were transfected into CHO cells. NKA-evoked increases in intracellular Ca(2+) were monitored by FLIPR. The potency of saredutant and ZD6021 was evaluated by their ability to inhibit NKA-induced increases in intracellular Ca(2+). NKA evoked increases in intracellular Ca(2+) with a potency ranging between 1 and 5nM in CHO cells expressing the different constructs. Saredutant and ZD6021 blocked NKA-evoked increases in intracellular Ca(2+) with pK(b) values ranging between 8.8-9.3 and 7.9-8.7, respectively. The current study demonstrates that polymorphisms leading to the Ile23Thr and Arg375His amino acid exchanges are highly prevalent in the human TACR2 gene. These polymorphisms however do not appear to affect the potency of the endogenous agonist NKA or the small molecule antagonists saredutant and ZD6021 with respect to intracellular Ca(2+) signalling.
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PMID:Occurrence and pharmacological characterization of four human tachykinin NK2 receptor variants. 1860 11


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