Design, synthesis, and structure–activity relationship of novel opioid κ-agonists

Kawai, Koji; Hayakawa, Jun; Miyamoto, Toru; Imamura, Yoshifumi; Yamane, Shinichi; Wakita, Hisanori; Fujii, H.; Kawamura, Kuniaki; Matsuura, Hirotoshi; Izumimoto, Naoki; Kobayashi, Ryosuke; Endo, Takashi; Nagase, Hiroshi

doi:10.1016/j.bmc.2008.09.011

Cited by 75 publications

(29 citation statements)

References 25 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…[14][15][16][17][18][19] Nalfurafine hydrochloride (Remitch capsules 2.5 μg; Toray Industries, Inc., Tokyo, Japan) is a selective κ-receptor agonist that was developed in 1992. In nonclinical studies, nalfurafine suppressed scratching behavior, 20,21 showed no drug dependence (unlike morphine, which agonizes the μ-receptor), [21][22][23][24] and, unlike the existing κ-receptor agonists, caused no aversion. 25 As such, it was considered to be a promising agent for the treatment of intractable pruritus in hemodialysis patients.…”

mentioning

confidence: 98%

Post-marketing surveillance study of the safety and efficacy of nalfurafine hydrochloride (Remitch<sup>® </sup>capsules 2.5 μg) in 3,762 hemodialysis patients with intractable pruritus

Kozono

Yoshitani

Nakano

2018

IJNRD

View full text Add to dashboard Cite

Background Intractable pruritus in hemodialysis patients can significantly decrease their quality of life and is also associated with poor vital prognosis. Although combined multiple causes of intractable pruritus in these patients have been identified, no existing treatments are proven to be sufficiently effective. We conducted a post-marketing surveillance to follow-up and assess the safety and efficacy of nalfurafine, a selective κ-opioid receptor agonist, for the treatment of intractable pruritus in patients undergoing hemodialysis. Patients and methods Hemodialysis patients with intractable pruritus from institutions in Japan who received oral nalfurafine hydrochloride between January 2010 and December 2013 were enrolled in the surveillance. Surveillance was completed in July 2015. Safety data during 1 year after nalfurafine treatment onset, and efficacy data of nalfurafine evaluating the first 12-week treatment period and the following period until 1 year after the initial dose of nalfurafine (using global assessment of the itch improvement by the physician, Visual Analog Scale, and the Shiratori’s severity scores) were collected and analyzed. Results In total, 3,762 patients were analyzed for safety. Adverse drug reactions were experienced by 402/3,762 (10.69%) patients. The most frequent adverse drug reactions were insomnia (127/3,762 [3.38%] patients), constipation (34 [0.90%]), somnolence (32 [0.85%]), dizziness (23 [0.61%]), nausea (13 [0.35%]), and malaise (9 [0.24%]). No patients developed dependence on nalfurafine. Nalfurafine was effective in 82.50% (2,880/3,491) of patients during the first 12 weeks and in 84.95% (2,167/2,551) on treatment during the subsequent period until 1 year after nalfurafine treatment initiation. Statistically significant decreases were reported in the Visual Analog Scale and the Shiratori’s severity scores ( p <0.001). Conclusion Oral nalfurafine hydrochloride (from 2.5 μg/day to a maximum of 5.0 μg/day) continues to be safe and effective for the treatment of intractable pruritus in hemodialysis patients in real-world clinical settings.

show abstract

mentioning

confidence: 98%

Post-marketing surveillance study of the safety and efficacy of nalfurafine hydrochloride (Remitch<sup>® </sup>capsules 2.5 μg) in 3,762 hemodialysis patients with intractable pruritus

Kozono

Yoshitani

Nakano

2018

IJNRD

View full text Add to dashboard Cite

show abstract

“…To the best of our knowledge, this was the first result that such simple trans-decahydroisoquinoline derivatives without an angular aryl group exhibited κ opioid receptor affinities and selectivities. [30][31][32] The angular hydroxy group in nalfurafine significantly influenced the κ selectivity, 3,8) whereas the angular substituent (H or OH) in decahydroisoquinoline derivatives 9 and 19 had minimal influence in the κ selectivity. Despite the presence of the same amide side chain with the same configuration as that of nalfurafine, the 6β-amide isomers 9b and 19b showed worse affinities and selectivities for the κ receptor than the corresponding 6α-amide compounds 9a and 19a.…”

mentioning

confidence: 99%

“…1) Narcotic addiction is believed to be derived from the μ receptor type, and therefore δ and κ types are promising drug targets for analgesics without addiction. To obtain ideal analgesics without addiction and other side effects derived from the μ receptor, we have synthesized various kinds of naltrexone derivatives and have reported selective ligands for κ [2][3][4][5][6][7][8][9] and δ [10][11][12][13][14] receptors. Quite recently, one of our designed κ selective agonists, nalfurafine hydrochloride (TRK-820, 2,3,6,8,9) Fig.…”

mentioning

confidence: 99%

Essential Structure of Opioid κ Receptor Agonist Nalfurafine for Binding to κ Receptor 1: Synthesis of Decahydroisoquinoline Derivatives and Their Pharmacologies

Nagase

Imaide

Yamada

et al. 2012

CHEMICAL & PHARMACEUTICAL BULLETIN

Self Cite

View full text Add to dashboard Cite

On the basis of the three-dimensional pharmacophore model of opioid κ agonists, we simplified the structure of nalfurafine (selective κ agonist) to find the essential structural moieties for binding the opioid receptors, especially κ receptor type. As a result, we found that the trans-fused decahydroisoquinoline derivatives without a phenol ring bound the opioid receptor in micromolar order and that both the amide side chain and the nitrogen substituted by the cyclopropylmethyl group were indispensable moieties for eliciting the κ selectivity. The simple decahydroisoquinoline without amide side chain also bound the opioid receptor without receptor type selectivity, suggesting that the message-address concept would be applicable to even these simple derivatives. These findings that the simple decahydroisoquinoline derivatives showed the affinities for the opioid receptors, especially some of the compounds showed κ selectivity, are the first example in the opioid field.Key words opioid; κ receptor; decahydroisoquinoline; nalfurafine; three-dimensional pharmacophore model Three types of opioid receptors (μ, δ, κ) are now well established not only by pharmacological studies but also by molecular biological studies.1) Narcotic addiction is believed to be derived from the μ receptor type, and therefore δ and κ types are promising drug targets for analgesics without addiction. To obtain ideal analgesics without addiction and other side effects derived from the μ receptor, we have synthesized various kinds of naltrexone derivatives and have reported selective ligands for κ 2-9) and δ [10][11][12][13][14] receptors. Quite recently, one of our designed κ selective agonists, nalfurafine hydrochloride 2,3,6,8,9) Fig. 1), was launched in Japan as an antipruritic for patients undergoing dialysis. 6,8,9) Although many arylacetamide derivatives such as U-50,488H 15,16) (Fig. 1) and U-69,593 17) were synthesized and developed as κ agonists, all of these derivatives were eliminated from clinical trials as not only analgesics but also as antipruritics because of their serious side effects like psychotomimetic and aversive reactions. 18,19) In contrast, nalfurafine has neither aversive nor addictive effects. 20) Our interest in the differences in the pharmacological effects between nalfurafine and the arylacetamide derivatives led us to conduct a detailed structure activity relationship investigation of nalfurafine derivatives. From these studies, we developed the hypothesis that in the active conformation of nalfurafine (Fig. 2), the C-ring would assume the boat form, thereby elevating the amide side chain to bind the κ receptor. 4,5,21,22) Based on this hypothesis, we designed and synthesized KNT-63 with an oxabicyclo[2.2.2] octane skeleton ( Fig. 1), and confirmed its high affinity for the κ receptor. 5) We also proposed a new three-dimensional pharmacophore model applicable to some κ agonists with various chemotypes. 21,22) Our new pharmacophore model of κ agonists supported the proposed active conformation of nalfurafine and...

show abstract

“…TRK-820, which has a structure different from arylacetamides, was first developed as an analgesic for postoperative pain, but the indication was changed to pruritus Nagase & Fujii, 2011). The rational drug design and synthesis of the compound have been reported (Kawai et al, 2008;Nagase et al, 1998;Nagase & Fujii, 2011); therefore, in this chapter, we will focus on its pharmacological properties. …”

Section: Introductionmentioning

confidence: 99%

Opioid Kappa Receptor Selective Agonist TRK-820 (Nalfurafine Hydrochloride)

Fujii¹,

Hirayama²,

Nagase³

2012

Pharmacology

Self Cite

View full text Add to dashboard Cite

Design, synthesis, and structure–activity relationship of novel opioid κ-agonists

Cited by 75 publications

References 25 publications

Post-marketing surveillance study of the safety and efficacy of nalfurafine hydrochloride (Remitch<sup>® </sup>capsules 2.5 μg) in 3,762 hemodialysis patients with intractable pruritus

Post-marketing surveillance study of the safety and efficacy of nalfurafine hydrochloride (Remitch<sup>® </sup>capsules 2.5 μg) in 3,762 hemodialysis patients with intractable pruritus

Essential Structure of Opioid κ Receptor Agonist Nalfurafine for Binding to κ Receptor 1: Synthesis of Decahydroisoquinoline Derivatives and Their Pharmacologies

Opioid Kappa Receptor Selective Agonist TRK-820 (Nalfurafine Hydrochloride)

Contact Info

Product

Resources

About

Design, synthesis, and structure–activity relationship of novel opioid κ-agonists

Cited by 75 publications

References 25 publications

Post-marketing surveillance study of the safety and efficacy of nalfurafine hydrochloride (Remitch<sup>&reg; </sup>capsules 2.5 &mu;g) in 3,762 hemodialysis patients with intractable pruritus

Post-marketing surveillance study of the safety and efficacy of nalfurafine hydrochloride (Remitch<sup>&reg; </sup>capsules 2.5 &mu;g) in 3,762 hemodialysis patients with intractable pruritus

Essential Structure of Opioid κ Receptor Agonist Nalfurafine for Binding to κ Receptor 1: Synthesis of Decahydroisoquinoline Derivatives and Their Pharmacologies

Opioid Kappa Receptor Selective Agonist TRK-820 (Nalfurafine Hydrochloride)

Contact Info

Product

Resources

About

Post-marketing surveillance study of the safety and efficacy of nalfurafine hydrochloride (Remitch<sup>® </sup>capsules 2.5 μg) in 3,762 hemodialysis patients with intractable pruritus

Post-marketing surveillance study of the safety and efficacy of nalfurafine hydrochloride (Remitch<sup>® </sup>capsules 2.5 μg) in 3,762 hemodialysis patients with intractable pruritus