Novel pharmacology: asimadoline, a κ‐opioid agonist, and visceral sensation

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Abstract
Abstract Asimadoline is a potent κ‐opioid receptor agonist with a diaryl acetamide structure. It has high affinity for the κ receptor, with IC50of 5.6 nmol L−1(guinea pig) and 1.2 nmol L−1(human recombinant), and high selectively with κ : μ : δ binding ratios of 1 : 501 : 498 in human recombinant receptors. It acts as a complete agonist inin vitroassay. Asimadoline reduced sensation in response to colonic distension at subnoxious pressures in healthy volunteers and in irritable bowel syndrome (IBS) patients without alteration of colonic compliance. Asimadoline reduced satiation and enhanced the postprandial gastric volume (in female volunteers). However, there were no significant effects on gastrointestinal transit, colonic compliance, fasting or postprandial colonic tone. In a clinical trial in 40 patients with functional dyspepsia (Rome II), asimadoline did not significantly alter satiation or symptoms over 8 weeks. However, asimadoline, 0.5 mg, significantly decreased satiation in patients with higher postprandial fullness scores, and daily postprandial fullness severity (over 8 weeks); the asimadoline 1.0 mg group was borderline significant. In a clinical trial in patients with IBS, average pain 2 h post‐on‐demandtreatment with asimadoline was not significantly reduced.Post hocanalyses suggest that asimadoline was effective in mixed IBS. In a 12‐week study in 596 patients,chronic treatmentwith 0.5 mg and 1.0 mg asimadoline was associated with adequate relief of pain and discomfort, improvement in pain score and number of pain‐free days in patients with IBS‐D. The 1.0 mg dose was also efficacious in IBS‐alternating. There were also weeks with significant reduction in bowel frequency and urgency. Asimadoline has been well tolerated in human trials to date.

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