Structure selectivity relationship studies of 17-cyclopropylmethyl-3,14β-dihydroxy-4,5α-epoxy-6β-[(4′-pyridyl)carboxamido]morphinan derivatives toward the development of the mu opioid receptor antagonists

Yuan, Yunyun; Elbegdorj, Orgil; Chen, Jianyang; Akubathini, Shashidhar Kumar; Beletskaya, Irina; Selley, Dana E.; Zhang, Yan

doi:10.1016/j.bmcl.2011.06.135

Cited by 19 publications

(19 citation statements)

References 40 publications

(35 reference statements)

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“…The pyridyl ring of NAP preferred to interact with the site A of the MOR owing to the π-π stacking interaction between the aromatic pyridyl ring and residue Trp318 7.35 and electrostatic interaction between the electron rich nitrogen atom of pyridyl ring and residue Lys303 6.58 . Since there was no positively charged residues in the KOR and DOR that could interact with electron rich nitrogen atom of pyridyl ring (Table 2), the binding affinities of NAP with KOR and DOR were much lower than that of NAP with the MOR 38, 39 . Therefore, we may conclude that both the aromaticity of the pyridine and the substituent at the pyridyl ring of NAP interacting with the residues in the ‘address’ domains influenced the binding of NAP to all three opioid receptors.…”

Section: Resultsmentioning

confidence: 99%

“…Based on the structure of lead compound NAP and its binding modes in the MOR, KOR, and DOR, our second generation MOR antagonists were designed, synthesized, and characterized 39 . Among these NAP derivatives, NMP and NGP (Figures 1b and 1c) were identified as the two most selective MOR antagonists, which showed comparable binding affinity, selectivity, and efficacy to NAP.…”

Section: Introductionmentioning

confidence: 99%

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Binding mode analyses of NAP derivatives as mu opioid receptor selective ligands through docking studies and molecular dynamics simulation

Wang

Zaidi

Zhang

2017

Bioorganic & Medicinal Chemistry

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Mu opioid receptor selective antagonists are highly desirable because of their utility as pharmacological probes for receptor characterization and functional studies. Furthermore, the mu opioid receptors act as an important target in drug abuse and addiction treatment. Previously, we reported NAP as a novel lead compound with high selectivity and affinity towards the mu opioid receptor. Based on NAP, we have synthesized its derivatives and further characterized their binding affinities and selectivity towards the receptor. NMP and NGP were identified as the two most selective MOR ligands among NAP derivatives. In the present study, molecular modeling methods were applied to assess the dual binding modes of NAP derivatives, particularly on NMP and NGP, in three opioid receptors, in order to analyze the effects of structural modifications on the pyridyl ring of NAP on the binding affinity and selectivity. The results indicated that the steric hindrance, electrostatic, and hydrophobic effects caused by the substituents on the pyridyl ring of NAP contributed complimentarily on the binding affinity and selectivity of NAP derivatives to three opioid receptors. Analyses of these contributions provided insights on future design of more potent and selective mu opioid receptor ligands.

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Section: Resultsmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

Binding mode analyses of NAP derivatives as mu opioid receptor selective ligands through docking studies and molecular dynamics simulation

Wang

Zaidi

Zhang

2017

Bioorganic & Medicinal Chemistry

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“…Then the prepared substituted isoquinoline-3-carboxylic acids or their saturated counterparts were coupled to 6α-NTA·2HCl using EDCI/HOBT method 33–35 . After treating the coupling mixture with K 2 CO 3 in methanol, the products were then purified by silica gel column chromatography with reasonable yields (Scheme 6).…”

Section: Resultsmentioning

confidence: 99%

Design, syntheses, and pharmacological characterization of 17-cyclopropylmethyl-3,14β-dihydroxy-4,5α-epoxy-6α-(isoquinoline-3′-carboxamido)morphinan analogues as opioid receptor ligands

Yuan

Zaidi

Stevens

et al. 2015

Bioorganic & Medicinal Chemistry

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A series of 17-cyclopropylmethyl-3,14β-dihydroxy-4,5α-epoxy-6α-(isoquinoline-3′-carboxamido)morphinan (NAQ) analogues were synthesized and pharmacologically characterized to study their structure-activity relationship at the mu opioid receptor (MOR). The competition binding assay showed two-atom spacer and aromatic side chain were optimal for MOR selectivity. Meanwhile, substitutions at the 1′- and/or 4′-position of the isoquinoline ring retained or improved MOR selectivity over the kappa opioid receptor while still possessing above 20-fold MOR selectivity over the delta opioid receptor. In contrast, substitutions at the 6′-and/or 7′-position of the isoquinoline ring reduced MOR selectivity as well as MOR efficacy. Among this series of ligands, compound 11 acted as an antagonist when challenged with morphine in warm-water tail immersion assay and produced less significant withdrawal symptoms compared to naltrexone in morphine-pelleted mice. Compound 11 also antagonized the intracellular Ca2+ increase induced by DAMGO. Molecular dynamics simulation studies of 11 in three opioid receptors indicated orientation of the 6’-nitro group varied significantly in the different “address” domains of the receptors and played a crucial role in the observed binding affinities and selectivity. Collectively, the current findings provide valuable insights for future development of NAQ-based MOR selective ligands.

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“…Due to the incidence of diarrhea at doses of 0.3 mg/kg and above, NAP might not be an ideal candidate for further development, but it may be able to serve as a lead to explore other novel agents 28 targeting opioid-induced bowel disfunction, such as constipation.…”

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confidence: 99%

6β-N-Heterocyclic substituted naltrexamine derivative NAP as a potential lead to develop peripheral mu opioid receptor selective antagonists

Yuan¹,

Stevens²,

Braithwaite³

et al. 2012

Bioorganic & Medicinal Chemistry Letters

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A 6β-N-heterocyclic substituted naltrexamine derivative, NAP, was proposed as a peripheral mu opioid receptor (MOR) selective antagonist based on the in vitro and in vivo pharmacological and pharmacokinetic studies. To further validate this notion, several functional assays were carried out to fully characterize this compound. In the charcoal gavage and intestinal motility assay in morphine-pelleted mice, when administered 0.3 mg/kg or higher doses up to 3 mg/kg subcutaneously, NAP significantly increased the intestinal motility compared to the saline treatment. The comparative opioid withdrawal precipitation study and the lower locomotor assay demonstrated that NAP showed only marginal intrinsic effect in the central nervous system either given subcutaneously or intravenously: no jumps were witnessed for the tested animals even given up to a dose of 50 mg/kg, while similar noticeable wet-dog shakes only occurred at the dose 50 times of those for naloxone or naltrexone, and significant reduction of the hyper-locomotion only happened at the dose as high as 32 mg/kg. Collectively, these results suggested that NAP may serve as a novel lead to develop peripheral MOR selective antagonist which might possess therapeutic potential for opioid-induced bowel dysfunction (OBD), such as opioid-induced constipation (OIC).

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Structure selectivity relationship studies of 17-cyclopropylmethyl-3,14β-dihydroxy-4,5α-epoxy-6β-[(4′-pyridyl)carboxamido]morphinan derivatives toward the development of the mu opioid receptor antagonists

Cited by 19 publications

References 40 publications

Binding mode analyses of NAP derivatives as mu opioid receptor selective ligands through docking studies and molecular dynamics simulation

Binding mode analyses of NAP derivatives as mu opioid receptor selective ligands through docking studies and molecular dynamics simulation

Design, syntheses, and pharmacological characterization of 17-cyclopropylmethyl-3,14β-dihydroxy-4,5α-epoxy-6α-(isoquinoline-3′-carboxamido)morphinan analogues as opioid receptor ligands

6β-N-Heterocyclic substituted naltrexamine derivative NAP as a potential lead to develop peripheral mu opioid receptor selective antagonists

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