# PubMed- The selective 5-HT1A antagonist, AZD7371 (robalzotan tartrate monohydrate), inhibits visceral pain-related visceromotor, but not autonomic car



## VSsupport (Feb 12, 2008)

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*The selective 5-HT1A antagonist, AZD7371 (robalzotan tartrate monohydrate), inhibits visceral pain-related visceromotor, but not autonomic cardiovascular, responses to colorectal distension in rats.*

J Pharmacol Exp Ther. 2009 Mar 26;

Authors: Lindstrom E, Ravnefjord A, Brusberg M, Hjorth S, Larsson H, Martinez V

5-hydroxytryptamine 1A (5-HT1A) receptors have been suggested as a target for the treatment of irritable bowel syndrome (IBS). A recent clinical trial investigating the efficacy of the selective 5-HT1A antagonist AZD7371 showed no symptomatic improvement in IBS patients. We characterized the mechanisms mediating potential analgesic effects of AZD7371 [3(R)-(N,N-Dicyclobutylamino)-8-fluoro-3,4-dihydro-2H-1-benzopyran-5-carboxamide (R,R)-tartrate monohydrate] in a model of colorectal distension (CRD)-induced visceral pain in rats to understand its mechanism of action and the lack of clinical efficacy. Visceromotor and cardiovascular responses (telemetry) were assessed in conscious rats during noxious CRD (80 mmHg). Effects of AZD7371 (3-300 nmol/kg, iv; 1-30 micromol/kg, po) and a reference 5-HT1A antagonist, WAY-100635 (3-300 nmol/kg, iv), were assessed. Effects of intracerebroventricular (ICV) AZD7371 were also evaluated. Intravenous AZD7371 or WAY-100635 and oral AZD7371 dose-dependently inhibited visceromotor responses to CRD (ED50s: 203 nmol/kg, 231 nmol/kg and 14 micromol/kg, respectively). In telemetrized rats, oral AZD7371 inhibited visceromotor responses to CRD without affecting the concomitant hypertensive and tachycardic responses. ICV AZD7371 did not affect visceromotor responses, while it inhibited micturition. None of the doses tested induced visible gross side-effects. AZD7371, likely acting at a spinal site, inhibited the visceromotor, but not the cardiovascular, responses to visceral pain in the CRD model in rats. While agents effective on multiple pain-related readouts in the CRD model (e.g. pregabalin or clonidine) alleviate IBS symptoms, AZD7371, effective on only one pain-related pseudo-affective readout, does not. Data from preclinical CRD models of visceral pain need to be interpreted cautiously as it relates to their clinical translational value.

PMID: 19325032 [PubMed - as supplied by publisher]

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