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Papers: 14 Mar 2020 - 20 Mar 2020


Animal Studies, Pharmacology/Drug Development


2020 Mar 13


J Pharmacol Exp Ther

Pharmacological Profile of Naldemedine, a Peripherally Acting μ-Opioid Receptor Antagonist: Comparison with Naloxone and Naloxegol.

Authors

Kanemasa T, Koike K, Takase K, Arai T, Nakamura A, Morioka Y, Hasegawa M
J Pharmacol Exp Ther. 2020 Mar 13.
PMID: 32169839.

Abstract

Opioid-induced constipation (OIC), a typical side effect of opioids, is due to activation of the μ-opioid receptors in the enteric nervous system. Peripherally acting μ-opioid receptor antagonists (PAMORAs) can reverse OIC by inhibiting the peripheral action of opioids without affecting centrally mediated analgesia. Naldemedine is a PAMORA with potent antagonist activity against μ-, δ-, and κ-opioid receptors. In this study, the pharmacological profiles of naldemedine, compared to those of naloxone and naloxegol, were evaluated. In vitro, Schild plot analysis indicated that naldemedine was a non-competitive antagonist of μ-opioid receptors, while other compounds were competitive antagonists. Also, naldemedine showed slower association and dissociation kinetics than the other compounds. In vivo, naldemedine dose-dependently ameliorated morphine-induced inhibition of small intestinal transit (SIT). The dose response curve was not sifted at 1 and 3 mg/kg morphine. On the contrary, that of naloxegol was significantly shifted to the right from 1 to 3 mg/kg morphine. In morphine-dependent rats, naldemedine caused peripheral withdrawal symptoms (diarrhea) at doses higher than 1 mg/kg, while the dose that produced half the maximal preventive effect (ED50) against constipation was 0.03 mg/kg. Naldemedine showed slower onset and a lesser severity of diarrhea than the other compounds at close to the ED50 value in the SIT model. Our results reveal that naldemedine has different pharmacological profiles (type of antagonism and binding kinetics) to the other compounds. This might explain the differential inhibition of morphine-induced SIT and withdrawal symptoms among the three antagonist compounds. SIGNIFICANCE STATEMENT: Naldemedine is a novel PAMORA with potent antagonist activity against μ-, δ-, and κ-opioid receptors. Naldemedine showed a non-competitive antagonism and slower association and dissociation kinetics against μ opioid receptors than naloxone and naloxegol. Naldemedine showed insurmountable antagonism of morphine-induced SIT inhibition and lower and slower peripheral withdrawal symptoms (diarrhea) than the other compounds. Therefore, naldemedine has a different pharmacological profile (the type of antagonism and binding kinetics) to the other compounds.