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

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 with those of naloxone and naloxegol, were evaluated. In vitro, Schild plot analysis indicated that naldemedine was a noncompetitive antagonist of µ-opioid receptors, whereas 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 shifted 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, whereas 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 peripherally acting µ-opioid receptor antagonist with potent antagonist activity against µ-, δ-, and κ-opioid receptors. Naldemedine showed a noncompetitive antagonism and slower association and dissociation kinetics against µ-opioid receptors than naloxone and naloxegol. Naldemedine showed insurmountable antagonism of morphine-induced 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.

Pharmacologic effects of naldemedine, a peripherally acting µ-opioid receptor antagonist, in in vitro and in vivo models of opioid-induced constipation.

BACKGROUND: Naldemedine (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. METHODS: The 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 RESULTS: Naldemedine 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 & INFERENCES: Naldemedine displayed potent binding affinity to, and antagonistic activity against, µ-, δ-, and κ-opioid receptors. Naldemedine tempered OIC in vivo without compromising opioid analgesia.

Absence of convulsive liability of doripenem, a new carbapenem antibiotic, in comparison with beta-lactam antibiotics.

beta-Lactam antibiotics have been suggested to have some degree of convulsive activity and neurotoxicity in experimental animals as well as in clinical situations. We examined the convulsive activities of a new carbapenem antibiotic, (+)-(4R,5S,6S)-6-[(1R)-1-hydroxyethyl]-4-methyl-7-oxo-3-[[(3S,5S)-5-[(sulfamoylamino)methyl]-3-pyrrolidinyl]thio]-1-azabicyclo[3.2.0]hept-2-ene-2-carboxic acid monohydrate (doripenem) using several animals and compared them with beta-lactam antibiotics. In intravenous (IV) injection studies, imipenem/cilastatin, at 400/400mg/kg produced seizure discharges on electroencephalogram (EEG) accompanied with clonic convulsions in rats. Meropenem showed only wet dog shaking behavior at 200 and 400mg/kg. Doripenem caused no changes in the EEG and behavior in rats at 400mg/kg. Imipenem/cilastatin IV potentiated the pentylenetetrazol (PTZ)-induced convulsions in mice at 250/250 mg/kg, while meropenem, panipenem/betamipron, cefazolin or doripenem did not cause any marked effects at up to 500 mg/kg. In mouse intracerebroventricular (ICV) injection studies, imipenem, panipenem and cefazolin induced clonic convulsions in a dose-dependent manner in mice. Doripenem and meropenem did not induce convulsions at up to 100 microg/mouse. In dog ICV injection studies, imipenem produced generalized seizure discharge with clonic convulsions at 100 microg/dog. Meropenem also produced spikes or seizure discharges at 100, 300 and 1,000 microg/dog. However, doripenem had no effects on the EEG and behavior in dogs at any doses. In in vitro binding studies, imipenem, panipenem, cefazolin and meropenem inhibited [(3)H]muscimol binding to the GABA(A) receptor in mouse brain homogenates while doripenem did not cause any inhibition at up to 10mM. In addition, doripenem had no influence on the anti-convulsant actions of valproic acid in the PTZ- or bicuculine-induced convulsive model. These results clearly indicate that doripenem has no convulsive activity, suggesting that its neurotoxicity may be negligible in clinical use.

2-Arylimino-5,6-dihydro-4H-1,3-thiazines as a new class of cannabinoid receptor agonists. Part 1: discovery of CB2 receptor selective compounds.

2-Arylimino-5,6-dihydro-4H-1,3-thiazines have been identified as a novel class of cannabinoid agonists. A lead structure with moderate activity was discovered through a high throughput screening assay. Structure-activity relationships led to the discovery of potent agonists of CB(2) receptor. The most potent compound 13 displays K(i) values of >5000 and 9 nM to CB(1) and CB(2) receptors, respectively.