Design, synthesis, and structure–activity relationship of novel opioid κ receptor selective agonists: α-Iminoamide derivatives with an azabicyclo[2.2.2]octene skeleton

Watanabe, Yoshikazu; Kitazawa, Shota; Fujii, H.; Nemoto, Toru; Hirayama, Shigeto; Iwai, Takashi; Gouda, Hiroaki; Hirono, Shuichi; Nagasea, Hiroshi

doi:10.1016/j.bmcl.2014.09.029

Cited by 9 publications

(4 citation statements)

References 20 publications

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“…To our notice, NFU elicits its analgesic effects via dual agonistic function at MOR/KOR, while it is also a DOR agonist with a moderate potency. Although some NFU derivatives have been synthesized and reported previously, many of these compounds have not been investigated or reported extensively in biological or pharmacological assays. − Taking its clinical success into consideration, NFU is an apparently preferred starting point to explore potential KOR/DOR agonists. Therefore, in the present work, we conducted a complementary structure–activity relationship (SAR) study to systematically understand the multi-opioid receptor pharmacology of NFU analogues in order to reveal potentially valuable information for developing dual KOR/DOR agonists.…”

Section: Introductionmentioning

confidence: 99%

Characterization of a Potential KOR/DOR Dual Agonist with No Apparent Abuse Liability via a Complementary Structure–Activity Relationship Study on Nalfurafine Analogues

Stevens

Arriaga

et al. 2022

ACS Chem. Neurosci.

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Discovery of analgesics void of abuse liability is critical to battle the opioid crisis in the United States. Among many strategies to achieve this goal, targeting more than one opioid receptor seems promising to minimize this unwanted side effect while achieving a reasonable therapeutic profile. In the process of understanding the structure−activity relationship of nalfurafine, we identified a potential analgesic agent, NMF, as a dual kappa opioid receptor/delta opioid receptor agonist with minimum abuse liability. Further characterizations, including primary in vitro ADMET studies (hERG toxicity, plasma protein binding, permeability, and hepatic metabolism), and in vivo pharmacodynamic and toxicity profiling (time course, abuse liability, tolerance, withdrawal, respiratory depression, body weight, and locomotor activity) further confirmed NMF as a promising drug candidate for future development.

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Section: Introductionmentioning

confidence: 99%

Characterization of a Potential KOR/DOR Dual Agonist with No Apparent Abuse Liability via a Complementary Structure–Activity Relationship Study on Nalfurafine Analogues

Stevens

Arriaga

et al. 2022

ACS Chem. Neurosci.

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“…Several NLF structure–activity relationship (SAR) explorations have been performed and reported. ,− However, systematic and comprehensive SAR reports on NLF are still missing from literature resources leading to numerous knowledge gaps. ,− To this end, we recently reported 7 NLF analogues that maintained the same carboxamide side chain at the C 6 -position of the epoxymorphinan skeleton as NLF itself . Herein, we further vary the C 6 -position carboxamide side chain to explore the SAR of this lead with a more robust data set (Figure ).…”

Section: Introductionmentioning

confidence: 99%

Systematic Structure–Activity Relationship Study of Nalfurafine Analogues toward Development of Potentially Nonaddictive Pain Management Treatments

St. Onge,

Pagare,

Zheng

et al. 2024

J. Med. Chem.

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Despite the availability of numerous pain medications, the current array of Food and Drug Administration-approved options falls short in adequately addressing pain states for numerous patients and consequently worsens the opioid crisis. Thus, it is imperative for basic research to develop novel and nonaddictive pain medications. Toward addressing this clinical goal, nalfurafine (NLF) was chosen as a lead and its structure−activity relationship (SAR) systematically studied through design, syntheses, and in vivo characterization of 24 analogues. Two analogues, 21 and 23, showed longer durations of action than NLF in a warm-water tail immersion assay, produced in vivo effects primarily mediated by KOR and DOR, penetrated the blood−brain barrier, and did not function as reinforcers. Additionally, 21 produced fewer sedative effects than NLF. Taken together, these results aid the understanding of NLF SAR and provide insights for future endeavors in developing novel nonaddictive therapeutics to treat pain.

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“…During the last years a broad range of novel κ agonists belonging to various different structural classes has been reported in the literature. − Recently, we have described decahydroquinoxaline κ-opioid receptor agonists representing conformationally restricted analogues of κ agonists U-50,488 ( 2 ) and GR-89,696 ( 3 ). − The relative and absolute configuration of decahydroquinoxaline-based κ ligands has a strong impact on their κ affinity. Whereas cis–cis -configured decahydroquinoxaline analogues show very low κ affinity, the trans–trans -configured diasteromer 4 represents a very potent κ agonist ( K i = 9.7 nM).…”

Section: Introductionmentioning

confidence: 99%

Design and Synthesis of Enantiomerically Pure Decahydroquinoxalines as Potent and Selective κ-Opioid Receptor Agonists with Anti-Inflammatory Activityin Vivo

Soeberdt

Molenveld²,

Storcken³

et al. 2017

J. Med. Chem.

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In order to develop novel κ agonists restricted to the periphery, a diastereo- and enantioselective synthesis of (4aR,5S,8aS)-configured decahydroquinoxalines 5-8 was developed. Physicochemical and pharmacological properties were fine-tuned by structural modifications in the arylacetamide and amine part of the pharmacophore as well as in the amine part outside the pharmacophore. The decahydroquinoxalines 5-8 show single-digit nanomolar to subnanomolar κ-opioid receptor affinity, full κ agonistic activity in the [S]GTPγS assay, and high selectivity over μ, δ, σ, and σ receptors as well as the PCP binding site of the NMDA receptor. Several analogues were selective for the periphery. The anti-inflammatory activity of 5-8 after topical application was investigated in two mouse models of dermatitis. The methanesulfonamide 8a containing the (S)-configured hydroxypyrrolidine ring was identified as a potent (K = 0.63 nM) and highly selective κ agonist (EC = 1.8 nM) selective for the periphery with dose-dependent anti-inflammatory activity in acute and chronic skin inflammation.

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Design, synthesis, and structure–activity relationship of novel opioid κ receptor selective agonists: α-Iminoamide derivatives with an azabicyclo[2.2.2]octene skeleton

Cited by 9 publications

References 20 publications

Characterization of a Potential KOR/DOR Dual Agonist with No Apparent Abuse Liability via a Complementary Structure–Activity Relationship Study on Nalfurafine Analogues

Characterization of a Potential KOR/DOR Dual Agonist with No Apparent Abuse Liability via a Complementary Structure–Activity Relationship Study on Nalfurafine Analogues

Systematic Structure–Activity Relationship Study of Nalfurafine Analogues toward Development of Potentially Nonaddictive Pain Management Treatments

Design and Synthesis of Enantiomerically Pure Decahydroquinoxalines as Potent and Selective κ-Opioid Receptor Agonists with Anti-Inflammatory Activityin Vivo

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