• Toshiyuki Kanemasa, Katsumi Koike, Tohko Arai, Hiroko Ono, Narumi Horita, Hiroki Chiba, Atsushi Nakamura, Yasuhide Morioka, Tsuyoshi Kihara, and Minoru Hasegawa.
• Neuroscience, Drug Discovery & Disease Research Laboratory, Shionogi & Co., Ltd., Osaka, Japan.
• Neurogastroenterol. Motil. 2019 May 1; 31 (5): e13563.

BackgroundNaldemedine (S-297995) is a peripherally acting μ-opioid receptor antagonist developed as a once-daily oral drug for opioid-induced constipation (OIC) in adults with chronic noncancer or cancer pain. This study characterized the pharmacological effects of naldemedine in vitro and in vivo.MethodsThe binding affinity and antagonist activity of naldemedine against recombinant human μ-, δ-, and κ-opioid receptors were assayed in vitro. Pharmacologic effects of naldemedine were investigated using animal models of morphine-induced inhibition of small and large intestinal transit, castor oil-induced diarrhea, antinociception, and morphine withdrawal.Key ResultsNaldemedine showed potent binding affinity and antagonist activities for recombinant human μ-, δ-, and κ-opioid receptors. Naldemedine significantly reduced opioid-induced inhibition of small intestinal transit (0.03-10 mg kg-1 ; P < 0.05) and large intestinal transit (0.3-1 μmol L-1 ; P < 0.05). Naldemedine (0.03-1 mg kg-1 ) pretreatment significantly reversed the inhibition of castor oil-induced diarrhea by subcutaneous morphine (P < 0.01). Naldemedine (1-30 mg kg-1 ) pretreatment (1 or 2 hours) did not alter the analgesic effects of morphine in a model measuring the latency of a rat to flick its tail following thermal stimulation. However, a significant delayed reduction of the analgesic effect of morphine was seen with higher doses of naldemedine (10-30 mg kg-1 ). Some centrally mediated and peripherally mediated withdrawal signs in morphine-dependent rats were seen with naldemedine doses ≥3 and ≥0.3 mg kg-1 , respectively.Conclusions & InferencesNaldemedine displayed potent binding affinity to, and antagonistic activity against, μ-, δ-, and κ-opioid receptors. Naldemedine tempered OIC in vivo without compromising opioid analgesia.© 2019 The Authors. Neurogastroenterology & Motility Published by John Wiley & Sons Ltd.

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