mdl-100907 and Irritable-Bowel-Syndrome

5-HT(2) receptors mediate a large array of physiological and behavioral functions in humans via three distinct subtypes: 5-HT(2A), 5-HT(2B)and 5-HT(2C). While selective 5-HT(2A)antagonists have been known for some time, knowledge of the precise role played by the 5-HT(2B)receptor was hampered by the existence of solely 5-HT(2B)5-HT(2C) mixed antagonists. However, selective 5-HT(2B)antagonists began recently to emerge in the literature. Indeed, four structural classes belonging to the piperazine, indole, naphthylpyrimidine and tetrahydro-beta-carboline scaffolds were reported. In this paper, we will briefly review the structural and pharmacological features of selective 5-HT(2B) antagonists, including patent literature of the last five years.

Topics: Animals; Binding, Competitive; Drug Design; Humans; Irritable Bowel Syndrome; Ligands; Migraine Disorders; Molecular Structure; Serotonin 5-HT2 Receptor Antagonists; Serotonin Antagonists

Here we employed structure-based ligand discovery techniques to explore a recently determined crystal structure of the 5-hydroxytryptamine 2B (5-HT2B) receptor. Ten compounds containing a novel chemical scaffold were identified; among them, seven molecules were active in cellular function assays with the most potent one exhibiting an IC50 value of 27.3 nM. We then systematically probed the binding characteristics of this scaffold by designing, synthesizing, and testing a series of structural modifications. The structure-activity relationship studies strongly support our predicted binding model. The binding profiling across a panel of 11 5-HT receptors indicated that these compounds are highly selective for the 5-HT2B receptor. Oral administration of compound 15 (30 mg/kg) produced significant attenuation of visceral hypersensitivity in a rat model of irritable bowel syndrome (IBS). We expect this novel scaffold will serve as the foundation for the development of 5-HT2B antagonists for the treatment of IBS.

Topics: Amino Acid Sequence; Animals; CHO Cells; Cricetinae; Cricetulus; Crystallography, X-Ray; Drug Design; Drug Evaluation, Preclinical; Irritable Bowel Syndrome; Models, Molecular; Molecular Sequence Data; Protein Binding; Rats; Receptor, Serotonin, 5-HT2B; Serotonin 5-HT2 Receptor Antagonists; Structure-Activity Relationship

Irritable bowel syndrome (IBS) is associated with an enhanced perception to visceral stimuli and exaggerated stress response. The serotonergic neurotransmitter system has been strongly implicated as a key player in the manifestation of IBS symptomatology including visceral hypersensitivity. However the role of 5-HT(2B) receptors in visceral pain, although speculated, is currently unclear. Thus we assessed the impact of a selective 5-HT(2B) receptor antagonist, RS-127445, on visceral hypersensitivity in a model of brain gut axis dysfunction the Wistar Kyoto (WKY) rat.. Colorectal distension (CRD) was used to assess the visceral sensitivity of the WKY rat compared to normosensitive Sprague Dawley (SD) rats. Once we verified the visceral sensitivity of the WKY rat we assessed the efficacy of RS-127445 in pain signalling from the colorectum. We administered the compound peripherally (i.p.) and centrally (i.c.v.) in order to ascertain the site of action of RS 127445. Behavioural responses to colorectal distention were then monitored.. The WKY rats were more viscerally hypersensitive than the SD as previously shown. RS-127445 (5 mg kg(-1), i.p.) significantly reversed visceral hypersensitivity in WKY animals. Moreover, when administered intracerebroventricularly RS-127445 (100 nM) also decreased the number of pain behaviours during noxious CRD in the WKY animals.. Taken together, blockade of 5-HT(2B) receptors offers an exciting novel therapeutic target for pain relief in stress-related gastrointestinal disorders such as IBS.

Topics: Analysis of Variance; Animals; Behavior, Animal; Disease Models, Animal; Hyperalgesia; Intestine, Large; Irritable Bowel Syndrome; Pain; Pain Measurement; Pain Threshold; Pyrimidines; Rats; Rats, Inbred WKY; Rats, Sprague-Dawley; Receptor, Serotonin, 5-HT2B; Serotonin 5-HT2 Receptor Antagonists; Serotonin Antagonists