Effects of the novel selective κ-opioid receptor agonist NP-5497-KA on morphine-induced reward-related behaviors.

Opioid addiction and the opioid overdose epidemic are becoming more serious, and the development of therapeutic agents is essential for the pharmacological treatment of substance use disorders. The κ-opioid receptor (KOP) is a member of the opioid receptor system that has been gaining attention as a promising molecular target for the treatment of numerous human disorders, including pain, depression, anxiety, and drug addiction. Here, we biologically and pharmacologically evaluated a novel azepane-derived ligand, NP-5497-KA, as a selective KOP agonist. NP-5497-KA had 1000-fold higher selectivity for the KOP over the µ-opioid receptor (MOP), which was higher than nalfurafine (KOP/MOP: 65-fold), and acted as a selective KOP full agonist in the 3',5'-cyclic adenosine monophosphate assay. The oral administration of NP-5497-KA (1-10 mg/kg) dose-dependently suppressed morphine-induced conditioned place preference in C57BL/6 J mice, and its effects were comparable to an intraperitoneal injection of nalfurafine (1-10 µg/kg). Nalfurafine (10 µg/kg) significantly inhibited rotarod performance, whereas NP-5497-KA (10 mg/kg) exerted no effect on rotarod performance. These results indicate that NP-5497-KA may be a novel option for the treatment of opioid use disorder with fewer side effects.

Design and synthesis of novel δ opioid receptor agonists with an azatricyclodecane skeleton for improving blood-brain barrier penetration.

We designed and synthesized novel δ opioid receptor (DOR) agonists 3a-i with an azatricyclodecane skeleton, which was a novel structural class of DOR agonists. Among them, 3b exhibited high values of binding affinity and potent agonistic activity for the DOR that were approximately equivalent to those of 2 which bore an oxazatricyclodecane skeleton. In vitro assays using the blood-brain barrier (BBB) permeability test kit supported the idea that 3b achieved an excellent BBB permeability by converting an oxygen atom of 2 to a carbon atom (methylene group) in the core skeleton. As a result, 3b showed potent antinociceptive effects.

Novel delta opioid receptor agonists with oxazatricyclodecane structure showing potent agonistic activities.

We recently reported oxazatricyclodecane derivatives 1 as δ opioid receptor (DOR) agonists having a novel chemotype, but their DOR agonistic activities were relatively low. Based on the working hypothesis that the dioxamethylene moiety in 1 may be an accessory site and that it may interfere with the sufficient conformational change of the receptor required for exerting the full agonistic responses, we designed and synthesized new oxazatricyclodecane derivatives 2-4 lacking the dioxamethylene moiety. As we expected, the designed compounds 2-4 showed pronouncedly improved agonistic activities for the DOR. Compound 2a with the 17-cyclopropylmethyl substituent was a potent agonist with the highest selectivity for the DOR and was expected to be a lead compound for novel and selective DOR agonists.

A novel IKKα inhibitor, noraristeromycin, blocks the chronic inflammation associated with collagen-induced arthritis in mice.

OBJECTIVES: To evaluate the therapeutic efficacy of a novel inhibitor for IκB kinase alpha (IKKα), noraristeromycin (NAM), for murine experimental model of rheumatoid arthritis, collagen- induced arthritis (CIA). METHODS: NAM has been chemically synthesized as reported earlier. CIA was induced in DBA/1JNCrlj mice by intradermal inoculation of bovine type II collagen (col II) together with Freund Complete Adjuvant. Following the Day 21 booster injection of col II with Freund Incomplete Adjuvant, the animals were monitored for the development of arthritis and clinically evaluated. NAM was administered orally at different doses prior to induction (prophylactic protocol) or after the emergence of definitive arthritis (therapeutic protocol). RESULTS: Here we demonstrate the experimental evidence that oral administration of NAM could completely prevent the occurrence of experimental arthritis in CIA mouse model at 0.3 mg/kg with ED50 value of approximately 0.1 mg/kg twice daily. Moreover, twice daily oral therapeutic dosage of 1 mg/kg of NAM significantly inhibited the paw swelling and disease progression even after the occurrence of experimental CIA. In addition, NAM exhibited an excellent pharmacokinetics in mice and oral administration of NAM could suppress the production of TNFα elicited by lipopolysaccharide (LPS) in a dose-dependent manner. CONCLUSIONS: These results indicated that IKKα inhibition is an effective novel therapy for the treatment of chronic inflammatory processes such as those associated with RA and other related conditions.

Agonist pharmacology at recombinant α1A - and α1L -adrenoceptors and in lower urinary tract α1 -adrenoceptors.

BACKGROUND AND PURPOSE: Two distinct α1 -adrenoceptor phenotypes (α1A and α1L ) have recently been demonstrated to originate from a single α1A -adrenoceptor gene. Here, we examined the agonist profiles of recombinant α1A and α1L phenotypes and of lower urinary tract (LUT) α1 -adrenoceptors. EXPERIMENTAL APPROACH: A series of drugs (A61603, Ro 115-1240, NS-49 , MK017 and ESR1150) originally developed for stress urinary incontinence (SUI) therapy were used to stimulate recombinant α1A - and α1L -adrenoceptor phenotypes, and their potencies and intrinsic activity estimated from Ca(2+) responses. Agonist-induced contractions were also examined in LUT tissues of rats and humans and in human mesenteric artery and rat tail artery. KEY RESULTS: All the drugs were potent agonists of the α1A -adrenoceptor compared with the α1L -adrenoceptor phenotype. Among them, Ro 115-1240 was shown to be an α1A -specific partial agonist that produced partial contractions through α1A -adrenoceptors in rat prostate and tail artery, but not in the other LUT tissues and human mesenteric artery. In contrast, P-come 102 showed full agonist activity at α1A - and α1L -adrenoceptors, but was less selective than noradrenaline for α1A -adrenoceptors. Like noradrenaline, P-come 102 was highly potent at inducing contractions in all of the LUT tissues tested. However, the potency and intrinsic activity of P-come 102 were significantly lower than those of noradrenaline in human mesenteric artery. CONCLUSIONS AND IMPLICATIONS: The α1A - and α1L -adrenoceptor phenotypes and LUT α1 -adrenoceptors were demonstrated to have distinct agonist profiles. As adrenergic contractions in LUT are predominantly mediated through α1L -adrenoceptors, the development of α1L -selective agonists may provide clinically useful drugs for SUI therapy.

Biological evaluation of novel benzisoxazole derivatives as PPARδ agonists.

We discovered novel peroxisome proliferator-activated receptor δ agonists with a characteristic benzisoxazole ring. Compound 5 exhibited potent human PPARδ transactivation activity. Furthermore, it stimulated the differentiation of oligodendrocyte precursor cells in vitro. This indicates that this potential drug may be effective for the treatment of demyelinating disorders such as multiple sclerosis.

Synthesis of a novel human PPARδ selective agonist and its stimulatory effect on oligodendrocyte differentiation.

We successfully synthesized a novel peroxisome proliferator-activated receptor (PPAR)δ selective agonist, namely, compound 20, with a characteristic benzisoxazole ring. Compound 20 exhibited potent human PPARδ transactivation activity and high δ selectivity. Further, it stimulated differentiation of primary oligodendrocyte precursor cells in vitro, indicating that it may be an effective drug in the treatment of demyelinating disorders such as multiple sclerosis.