Design and synthesis of KNT-127, a δ-opioid receptor agonist effective by systemic administration

Nagase, Hiroshi; Nemoto, Toru; Matsubara, Ayaka; Saito, Manabu; Yamamoto, Naoshi; Osa, Yumiko; Hirayama, Shigeto; Nakajima, Mayumi; Nakao, Kaoru; Mochizuki, Hidenori; Fujii, H.

doi:10.1016/j.bmcl.2010.08.083

Cited by 69 publications

(36 citation statements)

References 19 publications

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“…3,4,5,12,acridin-4a-yl]phenol), a heterocyclefused octahydroisoquinoline derivative, was reported to be a potent and selective DOPr agonist, capable of producing an antinociceptive effect with subcutaneous administration in an acetic acid and abdominal constriction assay . A TAN-67 analog, 39:6,7] morphinan-3,14b-diol), showed 7-fold higher DOPr binding affinity and 26-fold higher antinociceptive potency compared with its parent (Nagase et al, 2010). Structural modification of KNT-127 led to a DOPr agonist 39:6,89,) with a further improved in vitro activity profile (Ida et al, 2012).…”

Section: D-opioid Receptor Ligandsmentioning

confidence: 99%

Molecular Pharmacology ofδ-Opioid Receptors

et al. 2016

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Section: D-opioid Receptor Ligandsmentioning

confidence: 99%

Molecular Pharmacology ofδ-Opioid Receptors

et al. 2016

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“…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.…”

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.…”

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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

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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...

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“…ix KNT-127 177 produces systemic antinociceptive, antidepressant and anxiolytic activity without seizures, 110,178 and potent DOR agonist derivatives of KNT-127 also have been reported. 179 Additional DOR agonists, for example conformationally constrained analogues of SNC-80, have been reported.…”

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Delta opioid agonists: a concise update on potential therapeutic applications

Peppin

Raffa

2015

J Clin Pharm Ther

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SUMMARYWhat is known and objective: The endogenous opioid system co-evolved with chemical defences, or at times symbiotic relationships, between plants and other autotrophs and heterotrophic predators -thus, it is not surprising that endogenous opioid ligands and exogenous mimetic ligands produce diverse physiological effects. Among the endogenous opioid peptides (endomorphins, enkephalins, dynorphins and nociception/orphanin FQ) derived from the precursors encoded by four genes (PNOC, PENK, PDYN and POMC) are the pentapeptides Met-enkephalin (Tyr-Gly-Gly-Phe-Met) and Leu-enkephalin (Tyr-Gly-Gly-PheLeu). The physiological effects of the enkephalins are mediated via 7-transmembrane G protein-coupled receptors, including delta opioid receptor (DOR). We present a concise update on the status of progress and opportunities of this approach. Methods: A literature search of the PUBMED database and a combination of keywords including delta opioid receptor, analgesia, mood and individual compounds identified therein, from industry and other source, and from www.clinicaltrials.com. Results and discussion: DOR agonist and antagonist ligands have been developed with ever increasing affinity and selectivity for DOR over other opioid receptor subtypes and studied for therapeutic utility, primarily for pain relief, but also for other clinical endpoints. What is new and conclusion: Selective DOR agonists have been designed with a large increase in therapeutic window for a variety of potential CNS applications including pain, depression, and learning and memory among others. WHAT IS KNOWN AND OBJECTIVE

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Design and synthesis of KNT-127, a δ-opioid receptor agonist effective by systemic administration

Cited by 69 publications

References 19 publications

Molecular Pharmacology ofδ-Opioid Receptors

Molecular Pharmacology ofδ-Opioid Receptors

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

Delta opioid agonists: a concise update on potential therapeutic applications

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