Synthesis of quinolinomorphinan-4-ol derivatives as δ opioid receptor agonists

Ida, Yoshihiro; Nemoto, Toru; Hirayama, Shigeto; Fujii, H.; Osa, Yumiko; Imai, Masayuki; Nakamura, Takashi; Kanemasa, Toshiyuki; Kato, Akira; Nagase, Hiroshi

doi:10.1016/j.bmc.2011.11.047

Cited by 31 publications

(17 citation statements)

References 35 publications

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“…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). ARM100390 [N,N-diethyl-4-(phenylpiperidin-4-ylidenemethyl)-benzamide] (also known as ARM390), a compound structurally derived from SNC80, is a potent, highly selective, and stable DOPr agonist (Wei et al, 2000).…”

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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“…The assays were performed by a modification of a previously reported procedure. 14) Although all the synthesized compounds showed weak binding affinities for the opioid receptors (micromolar order affinities), N-cyclopropylmethyl (CPM) derivatives 9 and 19 had significant affinities and selectivities for the κ receptor. 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.…”

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confidence: 99%

“…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.…”

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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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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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“…The assays were performed by a previously reported procedure. 15 Although most of the tested compounds did not bind to the opioid receptors, 1b, 1c, and 8a exhibited submicromolar binding affinities to the MOR or to both the MOR and the KOR.…”

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Synthesis and Pharmacology of a Novel κ Opioid Receptor (KOR) Agonist with a 1,3,5-Trioxazatriquinane Skeleton

Hirayama

Wada

Nemoto

et al. 2014

ACS Med. Chem. Lett.

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We designed and synthesized the 1,3,5-trioxazatriquinane derivatives with m-hydroxyphenyl groups. These compounds include the phenethylamine structure within them, which is a common structure observed in morphinan derivatives like morphine. Among the synthesized compounds, (−)-8c with two m-hydroxyphenyl groups selectively bound and exerted full agonist activity toward the κ opioid receptor (KOR). Subcutaneously administered (−)-8c exhibited significant antinociceptive effects via the KOR in a dose-dependent manner. These results suggest the emergence of a novel class of KOR agonist.

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Synthesis of quinolinomorphinan-4-ol derivatives as δ opioid receptor agonists

Cited by 31 publications

References 35 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

Synthesis and Pharmacology of a Novel κ Opioid Receptor (KOR) Agonist with a 1,3,5-Trioxazatriquinane Skeleton

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