Verifying the role of 3-hydroxy of 17-cyclopropylmethyl-4,5α-epoxy-3,14β-dihydroxy-6β-[(4′-pyridyl) carboxamido]morphinan derivatives via their binding affinity and selectivity profiles on opioid receptors

Huang, Boshi; Gunta, Rama; Wang, Huiqun; Li, Mengchu; Cao, Danni; Mendez, Rolando E.; Gillespie, James C.; Chen, Chongguang; Huang, Lan-Hsuan M.; Liu‐Chen, Lee‐Yuan; Selley, Dana E.; Zhang, Yan

doi:10.1016/j.bioorg.2021.104702

Cited by 7 publications

(4 citation statements)

References 53 publications

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“…Eight enantiopure intermediates were required to prepare the target compounds. Part of the protocols to get these essential intermediate amines ( 1–8 ) were made available from previous studies from others and our lab, ,, and a systematic description for all synthetic routes is briefly discussed in the following. For preparing 1–8 , at least one stereoselective synthetic route was adopted and established with reasonable yields.…”

Section: Resultsmentioning

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: Resultsmentioning

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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“…Thus, NCP, with an A 50 value of 14.4 g/kg in the acetic acid writhing test has a higher potency than U50,488H and morphine, but lower than nalfurafine. NCP shows 6.5x selectivity for KOR over MOR in vitro and it is a full agonist at the KOR with partial agonist activity at the MOR (Huang et al, 2021;. We thus investigated whether NCP acts on KOR or MOR to produce analgesic effects.…”

Section: Ncp Produced Analgesic Effects Via the Kor With Higher Poten...mentioning

confidence: 99%

“…Zhang's lab has synthesized several series of 4,5-epoxymorphinan compounds. One of the compounds is 17-cyclopropylmethyl-3,14β-dihydroxy-4,5α-epoxy-6β-{[4′-(2′cyanopyridyl)]carboxamido}cmorphinan (NCP) , which has substitutions at the 6b position (Huang et al, 2021; (Fig. 1).…”

Section: Introductionmentioning

confidence: 99%

“…NCP displayed high affinities for the KOR and MOR with K i values of 0.13 and 1.25 nM, respectively, and had much lower affinity for the DOR (K i 75.3 nM). In in vitro [ 35 S]GTPS binding assay, NCP displayed potent KOR full agonist activity and MOR partial agonist activity (58% of the full agonist DAMGO) with EC 50 values of 0.28 nM and 1.82 nM, respectively, showing a selectivity ratio of 6.5 for the KOR over MOR (Huang et al, 2021;. NCP had a much lower potency at the DOR with high KOR/DOR selectivity (107x).…”

Section: Introductionmentioning

confidence: 99%

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NCP, a Dual Kappa and Mu Opioid Receptor Agonist, Is a Potent Analgesic Against Inflammatory Pain without Reinforcing or Aversive Properties

Huang,

Ho,

Cao

et al. 2024

J Pharmacol Exp Ther

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While agonists of  (MOR) and (KOR) opioid receptors have analgesic effects, they produce euphoria and dysphoria, respectively. Other side effects include respiratory depression and addiction for MOR agonists and sedation for KOR agonists. We reported that 17-cyclopropylmethyl-3,14β-dihydroxy-4,5αepoxy-6β-{[4′-(2′-cyanopyridyl)]carboxamido}cmorphinan (NCP) displayed potent KOR full agonist and MOR partial agonist activities (58%) with 6.5x KOR-over-MOR selectivity in vitro. Herein, we characterized pharmacological effects of NCP in rodents. In mice, NCP exerted analgesic effects against inflammatory pain in both the formalin test and the acetic acid writhing test, with A 50 values of 47.6 and 14.4 g/kg (s.c.), respectively. The analgesic effects in the acetic acid writhing test were mediated by the KOR. NCP at doses much higher than those effective in reducing inflammatory pain did not produce antinociception in the hot plate and tail flick tests, inhibit compound 48/80-induced scratching, cause conditioned place aversion (CPA) or preference, impair rotarod performance, inhibit locomotor activity, cause respiratory depression, or precipitate morphine withdrawal. However, NCP (10~100 g/kg) inhibited gastrointestinal transit with a maximum of ~40% inhibition. In MOR knockout mice, NCP caused CPA, demonstrating that its lack of CPA is due to combined actions on the MOR and KOR. Following s.c. injection, NCP penetrated into the mouse brain. In rats trained to selfadminister heroin, NCP (1~320 g/kg/infusion) did not function as a reinforcer. Thus, NCP produces potent analgesic effects via KOR without side effects except constipation. Therefore, dual full KOR/partial MOR agonists with moderate KOR-over-MOR selectivity may be promising as nonaddictive analgesics for inflammatory pain.

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Structural Characterization of KOR Inactive and Active States for 3D Pharmacology and Drug Discovery

Zaidi

Katritch

2021

The Kappa Opioid Receptor

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Verifying the role of 3-hydroxy of 17-cyclopropylmethyl-4,5α-epoxy-3,14β-dihydroxy-6β-[(4′-pyridyl) carboxamido]morphinan derivatives via their binding affinity and selectivity profiles on opioid receptors

Cited by 7 publications

References 53 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

NCP, a Dual Kappa and Mu Opioid Receptor Agonist, Is a Potent Analgesic Against Inflammatory Pain without Reinforcing or Aversive Properties

Structural Characterization of KOR Inactive and Active States for 3D Pharmacology and Drug Discovery

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