Modulation of Opioid Receptor Ligand Affinity and Efficacy Using Active and Inactive State Receptor Models

Anand, Jessica P.; Purington, Lauren C.; Pogozheva, Irina D.; Traynor, John R.; Mosberg, Henry I.

doi:10.1111/cbdd.12014

Cited by 22 publications

(58 citation statements)

References 37 publications

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“…The 3D structure of Rattus norvegicus μ-opioid receptor in active state was taken from Peptide Synthesis and Molecular Recognition Lab 35 . Coordinate files were subjected to Discovery Studio Visualizer for pre-docking receptor preparation.…”

Section: Resultsmentioning

confidence: 99%

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Design, synthesis, and biological evaluation of a series of bifunctional ligands of opioids/SSRIs

Mehr-un-Nisa

Munawar

Lee

et al. 2015

Bioorganic & Medicinal Chemistry

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A series of opioid and serotonin re-uptake inhibitors (SSRIs) bifunctional ligands have been designed, synthesized, and tested for their activities and efficacies at μ-, δ- and κ opioid receptors and SSRIs receptors. Most of the compounds showed high affinities for μ- and δ-opioid receptors and lower affinities for SSRIs and κ opioid receptors. A docking study on the μ-opioid receptor binding pocket has been carried out for ligands 3-11. The ligands 7 and 11 have displayed the highest binding profiles for the μ-opioid receptor binding site with ΔGbind (−12.14 kcal/mol) and Ki value (1.0 nM), and ΔGbind (−12.41 kcal/mol) and Ki value (0.4 nM), respectively. Ligand 3 was shown to have the potential of dual acting serotonin/norepinephrine re-uptake inhibitor (SNRI) antidepressant activity in addition to opioid activities, and thus could be used for the design of multifunctional ligands in the area of a novel approach for the treatment of pain and depression.

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Section: Resultsmentioning

confidence: 99%

“…The selected binding pockets of both receptor proteins included the important amino acid residues as indicated in the respective crystal structures. 35, 36 …”

Section: Resultsmentioning

confidence: 99%

Design, synthesis, and biological evaluation of a series of bifunctional ligands of opioids/SSRIs

Mehr-un-Nisa

Munawar

Lee

et al. 2015

Bioorganic & Medicinal Chemistry

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“…A study of flexible docking of carfentanil ( 3 ) and of the trans isomer of c-carfentanil ( 8b ) in their lowest-energy conformations was performed using Mosberg’s model of the MOR in the activated form 16 (Fig. 2).…”

Section: Resultsmentioning

confidence: 99%

“…16 A dielectric constant of one was used in the docking studies and in all subsequent calculations involving ligand-receptor complexes. Each of the resulting ligand-receptor complexes was minimized using the conjugate gradient approach.…”

Section: Methodsmentioning

confidence: 99%

‘Carba’-carfentanil (trans isomer): A μ opioid receptor (MOR) partial agonist with a distinct binding mode

Weltrowska¹,

Lemieux²,

Chung³

et al. 2014

Bioorganic & Medicinal Chemistry

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There is strong evidence to indicate that a positively charged nitrogen of endogenous and exogenous opioid ligands forms a salt bridge with the Asp residue in the third transmembrane helix of opioid receptors. To further examine the role of this electrostatic interaction in opioid receptor binding and activation, we synthesized ‘carba’-analogues of the highly potent μ opioid analgesic carfentanil (3), in which the piperidine nitrogen was replaced with a carbon. The resulting trans isomer (8b) showed reduced, but still significant MOR binding affinity (Kiμ = 95.2 nM) with no MOR versus DOR binding selectivity and was a MOR partial agonist. The cis isomer (8a) was essentially inactive. A MOR docking study indicated that 8b bound to the same binding pocket as parent 3, but its binding mode was somewhat different. A reevaluation of the uncharged morphine derivative N-formylnormorphine (9) indicated that it was a weak MOR antagonist showing no preference for MOR over KOR. Taken together, the results indicate that deletion of the positively charged nitrogen in μ opioid analgesics reduces MOR binding affinity by 2–3 orders of magnitude and may have pronounced effects on the intrinsic efficacy and on the opioid receptor selectivity profile.

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“…As a result, ligands that interact simultaneously with both MOR and DOR have been the subject of much research and many peptide, peptide-like, and alkaloid ligands have been described; however, few have the desired profile both in vitro and in vivo (Anand et al 2012; Anathan et al 2004; Balboni et al 2002; Bender et al 2015; Healy et al 2013; Purington et al 2011; Salvadori et al 1999; Schiller et al 1999). The peptide DIPPψNH 2 (Schiller et al 1999), the bivalent ligand MDAN-21 (Lenard et al 2007), and the multifunctional opioid alkaloid UMB425 (Healy et al 2013) all show some improvement over morphine in vivo , but both DIPPψNH 2 and UMB425 produce significant tolerance and dependence after chronic administration.…”

Section: Introductionmentioning

confidence: 99%

The behavioral effects of a mixed efficacy antinociceptive peptide, VRP26, following chronic administration in mice

et al. 2016

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Rationale VRP26 displays mu opioid receptor agonist and delta opioid receptor antagonist activity in vitro, a pharmacological profile purported to produce reduced tolerance, dependence, and rewarding effects. We hypothesized that VRP26 would display reduced adverse effects after chronic administration as compared with the traditional opioid analgesic fentanyl. Objective To explore the development of tolerance, dependence and conditioned place preference of VRP26 as compared with the traditional opioid analgesic fentanyl. Methods The antinociceptive effects of VRP26 and fentanyl were assessed using the mouse warm water tail withdrawal (WWTW) assay. Measurement of antinociceptive tolerance and physical dependence occurred after seven days of continuous administration of either fentanyl (0.3 mg/kg/day) or VRP26 (10 mg/kg/day); tolerance was measured by a shift in the antinociceptive dose response curve in the WWTW assay. Physical dependence was determined by observation of withdrawal symptoms after precipitated withdrawal. Rewarding effects were measured by the ability of VRP26 or fentanyl to produce conditioned place preference. Results Fentanyl produced significant tolerance and dependence, as well as significant conditioned place preference. VRP26 produced neither tolerance nor physical dependence, nor did it produce significant conditioned place preference. Conclusions These results suggest that chronic treatment with VRP26 may produce less tolerance or physical dependence than chronic treatment with clinically available mu opioid analgesics such as fentanyl. Additionally, VRP26 produces less rewarding effects than fentanyl. This desirable in vivo profile may be due to the mixed efficacy nature of VRP26 and could provide the framework for safer opioid analgesics.

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Modulation of Opioid Receptor Ligand Affinity and Efficacy Using Active and Inactive State Receptor Models

Cited by 22 publications

References 37 publications

Design, synthesis, and biological evaluation of a series of bifunctional ligands of opioids/SSRIs

Design, synthesis, and biological evaluation of a series of bifunctional ligands of opioids/SSRIs

‘Carba’-carfentanil (trans isomer): A μ opioid receptor (MOR) partial agonist with a distinct binding mode

The behavioral effects of a mixed efficacy antinociceptive peptide, VRP26, following chronic administration in mice

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