Abstract
The 5-hydroxytryptamine (5-HT; serotonin) 5-HT receptor represents a clinical target for antagonists to deliver symptomatic relief to patients with diarrhoea-predominant irritable bowel syndrome (IBS-d) or carcinoid syndrome. Unfortunately, this pharmacological strategy can present side effects (e.g. severe constipation). The present study investigates the potential of a novel 5-HT receptor partial agonist, CSTI-300, to treat patients with IBS-d, and other conditions associated with discomfort from colonic distension, with a predicted reduced side-effect profile. The and pre-clinical pharmacology of the drug CSTI-300 was investigated to explore the potential to treat patients with IBS-d. CSTI-300 displayed selective high affinity for the human (h) and rat (r) 5-HT receptor (K approximately 2.0 nM) and acted as a partial agonist (approximately 30-50% intrinsic efficacy) In an model of IBS-d, the rat colon distension model, CSTI-300 displayed dose-dependent efficacy. In addition, oral administration of CSTI-300 to dogs that achieved plasma levels of the drug exceeding the K value for the 5-HT receptor failed to either evoke emesis or alter the state of faeces. Pharmacokinetics for CSTI-300 in rat and dog identified high levels of oral availability with t range of 1.6-4.4 hours. The pre-clinical pharmacology of the Lead Candidate drug, CSTI-300, supports the potential of this novel drug to offer symptomatic relief to patients with IBS and carcinoid syndrome with a rationale for a reduced 'on-target' side-effect profile relative to 5-HT receptor antagonists such as alosetron. SIGNIFICANCE STATEMENT: There is a lack of effective current treatment for IBS-d and carcinoid syndrome, and in both conditions, over-activity of the 5-HT receptor is thought to be implicated in the pathophysiology. As 5-HT receptor blockade with antagonists results in significant side effects, we present evidence that treatment with a suitable 5-HT receptor partial agonist will alleviate some symptoms associated with these conditions yet without fully inhibiting the receptor predict a less pronounced side effect profile associated with this therapeutic strategy. [Abstract copyright: The American Society for Pharmacology and Experimental Therapeutics.]
Original language | English |
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Pages (from-to) | 122-134 |
Number of pages | 13 |
Journal | The Journal of Pharmacology and Experimental Therapeutics |
Volume | 373 |
Issue number | 1 |
Publication status | Published (VoR) - 26 Feb 2020 |
Keywords
- 5-HT receptors
- bowel disorders
- drug discovery
- gastrointestinal motility
- intestinal motility
- ligand gated ion channels