Efficacy of Naldemedine on Intestinal Hypomotility and Adhesions in Rodent Models of Postoperative Ileus.

Postoperative ileus (POI) often decreases patients' QOL because of prolonged hospitalization and readmission. Alvimopan, a peripheral µ-opioid receptor antagonist, is currently the only therapeutic drug for POI. The aim of this study was to examine the efficacy of naldemedine (a peripheral µ-opioid receptor antagonist with a non-competitive pharmacological profile different from that of alvimopan) on postoperative intestinal hypomotility and adhesion in rodent models, and compare it with the effects of alvimopan. Oral administration of naldemedine (0.3 mg/kg) and alvimopan (3 mg/kg) significantly inhibited the decrease in intestinal motility induced by mechanical irritation in mice (p < 0.01, for both). Naldemedine (1 mg/kg) significantly shortened the adhesion length in chemical-induced postoperative adhesion model rats (p < 0.05). Alvimopan (3 mg/kg) also significantly reduced the adhesion ratio (p < 0.01). These findings suggest that naldemedine is effective for postoperative intestinal hypomotility and adhesions in rodents (i.e., as for alvimopan). Thus, naldemedine may be a useful option for the treatment of POI.

Involvement of the Peripheral µ-Opioid Receptor in Tramadol-Induced Constipation in Rodents.

Tramadol is a weak opioid that produces analgesic effect via both the µ-opioid receptor (MOR) and non-opioid targets. Constipation is the most common opioid-related side effect in patients with cancer and non-cancer pain. However, the contribution of MOR to tramadol-induced constipation is unclear. Therefore, we used naldemedine, a peripherally acting MOR antagonist, and MOR-knockout mice to investigate the involvement of peripheral MOR in tramadol-induced constipation using a small intestinal transit model. A single dose of tramadol (3-100 mg/kg, per os (p.o.)) inhibited small intestinal transit dose-dependently in rats. Naldemedine (0.01-10 mg/kg, p.o.) blocked the inhibition of small intestinal transit induced by tramadol (30 mg/kg, p.o.) in rats. The transition rate increased dose-dependently over the range of naldemedine 0.01-0.3 mg/kg, and complete recovery was observed at 0.3-10 m/kg. Additionally, tramadol (30 and 100 mg/kg, subcutaneously (s.c.)) inhibited small intestinal transit in wild-type mice but not in MOR-knockout mice. These results suggest that peripheral MOR participates in tramadol-induced constipation.

Synthesis and Evaluation of in Vivo Anti-hypothermic Effect of the N- and C-Terminus Modified Thyrotropin-Releasing Hormone Mimetic: [(4S,5S)-(5-Methyl-2-oxooxazolidine-4-yl)carbonyl]-[3-(thiazol-4-yl)-L-alanyl]-L-prolinamide.

We explored orally effective thyrotropin-releasing hormone (TRH) mimetics, which show high central nervous system effects in structure-activity relationship studies based on in vivo antagonistic activity on reserpine-induced hypothermia (anti-hypothermic effect) in mice starting from TRH. This led us to the TRH mimetic: [(4S,5S)-(5-methyl-2-oxooxazolidine-4-yl)carbonyl]-[3-(thiazol-4-yl)-L-alanyl]-L-prolinamide 1, which shows a higher anti-hypothermic effect compared with that of TRH after oral administration. We next attempted further chemical modification of the N- and C-terminus of 1 to find more orally effective TRH mimetics. As a result, we obtained several N- and C-terminus modified TRH mimetics which showed high anti-hypothermic effects.

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.

Discovery of naldemedine: A potent and orally available opioid receptor antagonist for treatment of opioid-induced adverse effects.

Structure-activity relationship studies of several morphinan derivatives were conducted to obtain dual antagonists for µ- and δ-opioid receptors. We discovered peripherally restricted dual antagonists for µ/δ-opioid receptors as a new chemotype with a morphinan scaffold, which are orally available and do not easily pass the blood-brain barrier. As we expected, some of these compounds inhibit opioid-induced constipation and emesis/vomiting with limited potential to interfere the analgesic effects of morphine. Among them, naldemedine was selected as a potential drug candidate.

Preventive effects of naldemedine, peripherally acting µ-opioid receptor antagonist, on morphine-induced nausea and vomiting in ferrets.

AIMS: Naldemedine is a peripherally acting µ-opioid receptor antagonists (PAMORAs) indicated for the treatment of opioid-induced constipation (OIC). We investigated the preventive effect of naldemedine on morphine-induced nausea and vomiting in ferrets and conducted a pharmacokinetic/pharmacodynamic (PK/PD) analysis. MAIN METHODS: The antiemetic effect of naldemedine was evaluated as the frequency and time of retching (rhythmic abdominal contractile motion) and vomiting (throwing up vomit or similar reactions) caused by morphine in ferrets. After a single oral administration of naldemedine to ferrets, the plasma concentrations of naldemedine and morphine were measured by liquid chromatography-tandem mass spectrometry. KEY FINDINGS: Naldemedine showed a potent and dose-dependent anti-emetic effects against morphine-induced emetic responses, for up to 6 h. The dose of naldemedine that produced half the maximal effect (ED50) value for anti-emetic effect of naldemedine in the morphine-treated ferrets was 0.033 mg/kg. The PK/PD analysis revealed that the antiemetic effect was related to the plasma naldemedine concentration, with a half maximal effective concentration that produces half the maximal effect (EC50) of 3.51 ng/mL. The plasma concentration producing an antiemetic effect was almost 200-fold lower than that inducing an anti-analgesic effect in rats. SIGNIFICANCE: Naldemedine showed potent inhibition of morphine-induced vomiting for up to 6 h after dosing. These data suggest that naldemedine possesses antiemetic properties and could be effective against opioid-induced nausea and vomiting (OINV).

The antagonistic activity profile of naloxone in µ-opioid receptor agonist-induced psychological dependence.

Naloxone is a µ-opioid receptor antagonist that has been used to prevent overdose-related respiratory depression and deaths by the illicit use of opioids. Naloxone can also deter the abuse potential of opioids, but little has been reported regarding its antagonistic activity profile against opioid-induced psychological dependence. This study aimed to confirm the antagonistic activity profile of naloxone against several µ-opioid receptor agonists and investigate whether naloxone could affect the psychological dependence induced by widely used µ-opioid receptor agonist, oxycodone. In the Guanosine-5'-o-(3-thio) triphosphate (GTPγS) binding assay, naloxone (30-30,000 nM) inhibited the GTPγS binding induced by oxycodone, hydrocodone, morphine, and fentanyl. It elicited parallel rightward shifts in the concentration-response curves, indicating that naloxone possessed a competitive antagonistic activity profile against these µ-opioid receptor agonists. In the conditioned place preference test, oxycodone (0.01-1 mg/kg, i.v.) produced dose-dependent increases in place preference. The increased place preference induced by oxycodone (1 mg/kg) was significantly attenuated by co-administration of naloxone at a dose of 0.5 mg/kg but not 0.01 mg/kg. Naloxone (0.5 mg/kg, i.v.) also blocked oxycodone (1 mg/kg)-induced dopamine release in nucleus accumbens; however, at a lower dose (0.01 mg/kg), it did not affect the intrinsic dopamine release by oxycodone. These results indicate that the psychological dependence of oxycodone could be antagonized by naloxone, depending on the dose. This characterization might lead to a better understanding of the competitive antagonistic activity profile of naloxone for µ-opioid receptor in the brain.

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.

Correction to Discovery of the Orally Effective Thyrotropin-Releasing Hormone Mimetic: 1-{N-[(4S,5S)-(5-Methyl-2-oxooxazolidine-4-yl)carbonyl]-3-(thiazol-4-yl)-l-alanyl}-(2R)-2-methylpyrrolidine Trihydrate (Rovatirelin Hydrate).

[This corrects the article DOI: 10.1021/acsomega.8b01481.].

2-Arylimino-5,6-dihydro-4H-1,3-thiazines as a new class of cannabinoid receptor agonists. Part 3: Synthesis and activity of isosteric analogs.

Structure-activity relationships and efforts to optimize the pharmacokinetic profile of isosteric analogs of 2-arylimino-5,6-dihydro-4H-1,3-thiazines as cannabinoid receptor agonists are described. Among those examined, compound 25 showed potent affinity for cannabinoid receptor 1 (CB1) and receptor 2 (CB2). This compound displayed oral bioavailability and analgesic activity.

Discovery of the Orally Effective Thyrotropin-Releasing Hormone Mimetic: 1-{N-[(4S,5S)-(5-Methyl-2-oxooxazolidine-4-yl)carbonyl]-3-(thiazol-4-yl)-l-alanyl}-(2R)-2-methylpyrrolidine Trihydrate (Rovatirelin Hydrate).

We have explored orally effective thyrotropin-releasing hormone (TRH) mimetics, showing oral bioavailability and brain penetration by structure-activity relationship (SAR) study on the basis of in vivo antagonistic activity on reserpine-induced hypothermia in mice. By primary screening of the synthesized TRH mimetics, we found a novel TRH mimetic: l-pyroglutamyl-[3-(thiazol-4-yl)-l-alanyl]-l-prolinamide with a high central nervous system effect compared with TRH as a lead compound. Further SAR optimization studies of this lead compound led to discovery of a novel orally effective TRH mimetic: 1-{N-[(4S,5S)-(5-methyl-2-oxooxazolidine-4-yl)carbonyl]-3-(thiazol-4-yl)-l-alanyl}-(2R)-2-methylpyrrolidine trihydrate (rovatirelin hydrate), which was selected as a candidate for clinical trials.

[Pharmacological profiles of benzodiazepinergic hypnotics and correlations with receptor subtypes].

We examined the behavioral pharmacological properties of six benzodiazepine (omega) receptor ligands including brotizoram, nitrazepam, quazepam, rilmazafone, zolpidem and zopiclone and the binding of these drugs with omega receptor subtypes. Behavioral tests were performed at the time of the maximal effects induced by each drug following its oral administration to mice. All of these drugs dose-dependently induced impairment of motor coordination as rotarod performance and potentiation of thiopental-induced anesthesia as hypnotic effect. The hypnotic effects of rilmazafone, whose major metabolites were bound to both omega1 and omega2 receptors with high affinity, and omega1 selective quazepam were about 20 times more effective than the induction of motor impairments when compared with ED50 values. However, there was no difference between the ED50 values of omega1 selective zolpidem alone in these two tests. An antianxiety efficacy of zolpidem was relatively weak unlike that of other drugs in the elevated plus-maze. It has been reported that omega2, but not omega1, receptors are associated with motor impairment and anxiolytic effect. The weak anxiolytic effect of zolpidem supports the previous hypothesis. However, the strong motor incoordination of zolpidem suggests that not only omega2 but also omega1 receptors are related to motor impairment unlike the previous hypothesis.

Distinct relations among plasma concentrations required for different pharmacological effects in oxycodone, morphine, and fentanyl.

Several clinical reports showed that adverse effect profiles are not the same in morphine, oxycodone, and fentanyl. The authors investigated whether the relationship between plasma concentrations for antinociceptive effect and for various pharmacological effects differed among oxycodone, morphine, and fentanyl under controlled experimental setting using animal models. Oxycodone induced constipation and an antinociceptive effect in a similar concentration-dependent manner, whereas morphine required approximately 9-fold higher plasma concentration for antinociceptive effect compared with that for constipation when 50% effective plasma concentration (EC(50)) levels were compared. The EC(50) values for inhibition of behavioral activity were 2.1-, 2.7-, and 1.3-fold higher than those for antinociceptive effect in oxycodone, morphine, and fentanyl, respectively. Respiratory inhibition was observed even at higher plasma concentrations in all three opioids, and the differences in the EC(50) values compared with those for antinociceptive effects were 234.5-fold (oxycodone), 233.1-fold (morphine), or 104.2-fold (fentanyl). These results showed that oxycodone, morphine, and fentanyl exhibited unique patterns of plasma concentrations required for different pharmacological effects. The different adverse effect profiles observed in a clinical setting appear to be resulted from, at least in part, distinct intrinsic pharmacological profiles among these µ-opioid receptor agonists.

Questionnaire survey of hospitals in Saitama Prefecture regarding the shortage of 99mTc-labeled radiopharmaceuticals and 99Mo/99mTc generators.

OBJECTIVE AND METHODS: A questionnaire survey was conducted at all 32 hospitals in Saitama Prefecture to investigate the current difficult situation in terms of nuclear medicine management in the face of the (99m)Tc shortage due to insufficient supply, and 29 hospitals (90.6%) replied. RESULTS: Of the 29, 15 (51.7%) reported a reduction in the number of nuclear medicine studies performed due to the shortage of supply, although the reduction was small. The decrease per month was less than 20 studies in 73% of the institutions. Of the nuclear medicine studies that involve the use of (99m)Tc, the studies whose reduction in number most seriously affected patient management were, in decreasing order: (99m)Tc-MAA lung perfusion scans, (99m)Tc-MAG(3), (99m)Tc-DTPA, or (99m)Tc-DMSA renoscans, (99m)Tc-MDP bone scans, (99m)Tc-HMPAO or ECD brain SPECT studies, (99m)Tc-MIBI or tetrofosmin myocardial SPECT studies, (99m)Tc-radiocolloid sentinel lymphoscintigraphy, (99m)Tc-HSA-D or pyrophosphate bleeding scans, (99m)Tc-GSA hepatic function reserve scans, and (99m)Tc-MIBI parathyroid scans. The reduction is probably ascribable to factors such as cancellations of emergency studies, absence of substitute studies, sequential studies using the same radiopharmaceutical, and higher cost of the syringe-type products than the vial-type products. Substitutes for (99m)Tc studies were performed at 52% (15/29) of the institutions. Myocardial perfusion imaging with (201)Tl chloride was the most common substitute study. CONCLUSIONS: The results of this survey suggested the several procedures to resolve the issues related to the shortage. The staffs at all institutions except one gave the impression that their nuclear medicine ordering systems had been greatly affected by the shortage of supply. This adverse circumstance, however, may provide a good opportunity to educate the public about nuclear medicine studies that use (99m)Tc and SPECT, with which citizen are now unfamiliar.

Morphine, oxycodone, and fentanyl exhibit different analgesic profiles in mouse pain models.

Morphine, oxycodone, and fentanyl are clinically prescribed drugs for the management of severe pain. We investigated whether these opioids possess different efficacy profiles on several types of pain in mouse pain models. When the three opioids were tested in the femur bone cancer model, all of them significantly reversed guarding behavior, whereas the effects on limb-use abnormality and allodynia-like behavior differed among the opioids. Particularly, although oxycodone (5 - 20 mg/kg) and fentanyl (0.2 mg/kg) significantly reversed limb-use abnormality, not even a high dose of morphine (50 mg/kg) could reverse it. When the effects of these opioids were examined in a sciatic nerve ligation (SNL) model of neuropathic pain, oxycodone was the most effective, producing an antinociceptive effect without affecting the withdrawal threshold of sham-treated animals. When the effects of these opioids were examined with the tail-flick test using naive animals, oxycodone, morphine, and fentanyl exhibited antinociceptive effects on thermal nociception. These results show that the three opioids exhibit different efficacy outcomes in multiple pain models and that the efficacy profile of oxycodone does not overlap those of morphine and fentanyl.

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

Structure-activity relationships and efforts to optimize the pharmacokinetic profile of a class of 2-arylimino-5,6-dihydro-4H-1,3-thiazines as cannabinoid receptor agonists are described. Among the compounds examined, compound 14 showed potent affinity and high selectivity for CB2, and compound 23 showed potent affinities against CB1 and CB2. These compounds displayed oral bioavailability.