Ko Hasebe

Possible Pharmacotherapy of the Opioid κ Receptor Agonist for Drug Dependence

Abstract: Because there are few efficacious medications for drug dependence, many clinical trials are being conducted in earnest to find such medications. Considerable evidence has shown that opioid κ receptor agonists attenuate several behavioral responses induced by drugs of abuse. Although this raises the possibility that opioid κ receptor agonists may be useful for the treatment of drug dependence on drugs of abuse, it has been previously reported that treatment with selective opioid κ receptor agonists causes a psychotomimetic effect and dysphoria both in clinical studies and experimental animal models. As a result, we found the novel opioid κ receptor agonist TRK‐820, another chemical class of opioid κ receptor agonist that has a morphinan scaffold unlike prototypical opioid κ receptor agonists, by application of a modified message‐address concept. TRK‐820 showed high selectivity for an opioid κ receptor, and strong agonistic activity in both in vitro and in vivo experiments. Like other opioid κ receptor agonists, TRK‐820 could markedly suppress the rewarding effects induced by morphine and cocaine and the discriminative stimulus effect of cocaine. Furthermore, TRK‐820 attenuated the mecamylamine‐precipitated nicotine‐withdrawal aversion in a conditioned place preference paradigm. It is worthwhile to note that unlike prototypical opioid κ receptor agonists, TRK‐820 failed to produce a significant place aversion in rodents at doses that were sufficient to produce significant antinociception. Taken together, these findings indicate that TRK‐820 may be useful for the treatment of drug dependence without any aversive effects.

Synthesis of a Stable Iminium Salt and Propellane Derivatives

The treatment of morphinan 1 with NaH and MsCl provided very stable iminium salt 7 possessing propellane skeleton. One of the synthesized iminium salts 7, isobutyl derivative 7b, was crystallized and its structure was determined by X-ray crystallography. The natural bond orbital analysis suggested that the stability of the iminium should result from the stereoelectronic effect (hyperconjugation) attributed to their own structures.

Drug design and synthesis of a novel κ opioid receptor agonist with an oxabicyclo[2.2.2]octane skeleton and its pharmacology

A conformational analysis of kappa opioid receptor agonists, TRK-820 and U-50,488H indicated an active conformation of TRK-820 in which the C-ring was in the boat form with the 14-OH interacting with the amide nitrogen. Based on the obtained active conformation of TRK-820, we designed and synthesized a novel kappa agonist KNT-63 with oxabicyclo[2.2.2]octane skeleton. KNT-63 showed profound antinociceptive effects via the kappa receptor which were as potent as that of TRK-820.

Involvement of mitogen-stimulated p70-S6 kinase in the development of sensitization to the methamphetamine-induced rewarding effect in rats

The neural plasticity associated with behavioral sensitization following repeated administration of a psychostimulant methamphetamine (METH) is thought to require synthesis of new proteins. The aim of the present study was to investigate the role of p70-S6 kinase (p70-S6K) phosphorylation, which contributes to the selective translation of a unique family of mRNA, in mediating both the METH-induced rewarding effect and its sensitization. An intra-nucleus accumbens (N.Acc.) pre-injection with 0.025 pmol/rat of a selective p70-S6K inhibitor rapamycin failed to affect the METH-induced conditioned place preference. However, this treatment clearly abolished the development of sensitization of the METH-induced conditioned place preference. Consistent with the behavioral assay, the level of the immunoreactivity of phosporylated-p70-S6K was not changed in the cytosolic fraction of the N.Acc. obtained from rats that had revealed the METH-induced rewarding effect. In contrast, the immunoreactivities in the cytosolic preparation for Western blotting and immunohistochemical density of phosphorylated-p70-S6K were significantly increased in the N.Acc. obtained from METH-sensitized rats as compared with those with chronic saline treatment. However, the immunoreactivities of phosphorylated-extracellular signal-regulated kinase and phosphorylated-ribosomal S6 protein were not significantly altered in the N.Acc. under the same condition. The present data provide evidence for the change in the translation rate, which can be regulated by S6K phosphorylation, in the N.Acc. during the development of sensitization to METH-induced rewarding effects in rats.

Effects of a novel β3‐adrenoceptor agonist, AJ‐9677, on relaxation of the detrusor muscle: An in vitro study

Objectives:  To examine the relaxant effects of AJ‐9677, a novel β3‐adrenoceptor agonist, on the isolated rat, monkey and human detrusor muscle.

Pharmacological effect of TRK-380, a novel selective human β3-adrenoceptor agonist, on mammalian detrusor strips.

OBJECTIVE To clarify the potential of TRK-380 as a drug for overactive bladder in humans by evaluating the agonistic activities for human β-adrenergic receptors (β-ARs) and the relaxing effects on isolated detrusor strips. METHODS The agonistic activities for human β-ARs were evaluated in SK-N-MC cells (for human β(3)-ARs) and Chinese hamster ovary cells expressing human β(1)- or human β(2)-ARs using the cyclic adenosine monophosphate accumulation assay. The relaxing effects on the resting tension in isolated detrusor strips from humans, monkeys, dogs, and rats and on carbachol- or KCl-induced contractions in human detrusor strips were evaluated. RESULTS In the cyclic adenosine monophosphate accumulation assay, the agonistic activity of TRK-380 for human β(3)-ARs was potent and equivalent to that of the potent nonselective β-AR agonist isoproterenol and superior to that of selective β(3)-AR agonists, such as BRL-37344 and CL316,243. TRK-380 showed no agonistic activity for human β(1)-ARs and a weak agonistic effect on human β(2)-ARs. In isolated detrusor strips, the concentration-dependent relaxing effects of TRK-380 on the resting tension were equivalent to those of isoproterenol in humans, monkeys, and dogs but weaker than the effects in rats. The selective β(3)-AR antagonist SR59230A shifted the concentration-response curve in a concentration-dependent manner to TRK-380 for the resting tension of human detrusor strips to the right. TRK-380 had a concentration-dependent relaxing effect on the contractile responses to carbachol and KCl in human detrusor strips. CONCLUSION TRK-380 was a potent and selective human β(3)-AR agonist, and the isolated human detrusor relaxation was mainly mediated by activation of the β(3)-AR. Consequently, TRK-380 might be a promising compound for the treatment of overactive bladder.

Synthesis of N-isobutylnoroxymorphone from naltrexone by a selective cyclopropane ring opening reaction.

Selective ring opening reaction of the N-cyclopropylmethyl group in naltrexone (1d) was effected in the presence of platinum (IV) oxide and hydrobromic acid under a hydrogen atmosphere at rt to selectively afford N-isobutyl derivative 10. The binding affinity of N-i-Bu derivative 10 for opioid receptors was 11-17 times less than that of the corresponding N-CPM compound, naltrexone (1d). However, compound 10 showed dose-dependent analgesic effects. Contrary to expectations based on previous structure-activity relationship studies for a series of N-substituted naltrexone derivatives that compound 10 would be an opioid antagonist, 10 showed dose-dependent analgesia in the mouse acetic acid writhing test (ED(50): 5.05 mg/kg, sc), indicating it was an opioid agonist. This finding may have a great influence on the drug design of opioid agonists.

Aerobic oxidation of indolomorphinan without the 4,5-epoxy bridge and subsequent rearrangement of the oxidation product to spiroindolinonyl-C-normorphinan derivative

Aerobic oxidation of indolomorphinan 1 without a 4,5-epoxy bridge proceeded in the presence of platinum catalyst to give indoleninomorphinan 2 or quinolono-C-normorphinan 5. The 4-hydroxy group would play an important role in deciding the course of the reaction. Treatment of 2a with 1,8-diazabicyclo[5.4.0]undec-7-ene (DBU) gave spiroindolinonyl-C-normorphinan 3a whose structure resembles that of delta opioid receptor agonist spiroindanyloxymorphone (SIOM). Boron trichloride was effective for the reverse reaction from 3a to 2a without side reaction. This practical interconversion method between hydroxyindolenine and spiroindolinone would be useful for the design and construction of drug-like compound libraries. Although the compound 3b was expected to show the selectivity for delta opioid receptor because of the structural resemblance to SIOM, it was rather selective for 1 opioid receptor (1: K(i)=0.75nM; delta: K(i)=2.90nM; kappa: K(i)=13.4nM). The result suggests that the slight difference of the spatial location of the benzene rings in these compounds may definitively affect the binding affinity for delta opioid receptor.

Synthesis of new opioid derivatives with a propellane skeleton and their pharmacology: part 1.

The observation that 17-cyclopropylmethylmorphinan derivatives without the 4,5-epoxy ring showed more κ selectivity than those with a 4,5-epoxy ring led us to develop a working hypothesis: the position of the plane composed of the A and B rings would influence the opioid receptor type selectivity and that the decrease in the torsion angle C11-C12-C13-C14 could improve the κ selectivity. Consistent with our hypothesis, KNT-42 with an N-cyclopropylmethyl propellane structure, whose A and B rings were fixed in a torsion angle of approximately 0°, showed κ selective agonist activity.

Novel synthesis of a 1,3,5-trioxazatriquinane skeleton using a nitrogen clamp.

An alpha-hydroxyaldehyde derived from naltrexone was converted to an oxazoline dimer with ammonium chloride and sodium acetate in MeOH under reflux. The resulting dimer was treated with dl-camphorsulfonic acid in CHCl(3) to give the trimer. The method for trimer synthesis was also applied to general alpha-hydroxyaldehydes to afford trimers in good yield.