Chemotype-selective Modes of Action of κ-Opioid Receptor Agonists

Vardy, Eyal; Mosier, Philip D.; Frankowski, Kevin J.; Wu, Huixian; Katritch, Vsevolod; Westkaemper, Richard B.; Aubé, Jeffrey; Stevens, Raymond C.; Roth, Bryan L.

doi:10.1074/jbc.m113.515668

Cited by 62 publications

(160 citation statements)

References 44 publications

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“…In addition, it has been found that virtual screening for ligands using inactive-state GPCRs can produces agonist leads (see for example Negri et al) [27]. We have previously described a putative binding mode for salvinorin A representing an initial recognition mode based on an extensive amount of experimental data [9,28]. This binding mode was reproduced in the current docking studies and is shown in Figure 3a.…”

Section: Molecular Modelingsupporting

confidence: 56%

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Michael Acceptor Approach to the Design of New Salvinorin A- Based High Affinity Ligands to the Kappa-Opioid Receptor

Polepally¹,

Setola²,

Vardy³

et al. 2012

Planta Med

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The neoclerodane diterpenoid salvinorin A is a major secondary metabolite isolated from the psychoactive plant Salvia divinorum. Salvinorin A has been shown to have high affinity and selectivity for the κ-opioid receptor (KOR). To study the ligand-receptor interactions that occur between salvinorin A and the KOR, a new series of salvinorin A derivatives bearing potentially reactive Michael acceptor functional groups at C-2 was synthesized and used to probe the salvinorin A binding site. The κ-, δ-, and μ-opioid receptor (KOR, DOR and MOR, respectively) binding affinities and KOR efficacies were measured for the new compounds. Although none showed wash-resistant irreversible binding, most of them showed high affinity for the KOR, and some exhibited dual affinity to KOR and MOR. Molecular modeling techniques based on the recently-determined crystal structure of the KOR combined with results from mutagenesis studies, competitive binding, functional assays and structure-activity relationships, and previous salvinorin A-KOR interaction models were used to identify putative interaction modes of the new compounds with the KOR and MOR. Supporting informationScatter plot of pK i vs. pIC 50 at KOR for salvinorin A and tested analogs, 1 H, 13 C NMR spectra and chromatographic (HPLC) data for synthesized compounds 4a-4h and 5a-5n are presented in the Supporting Information.

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Section: Molecular Modelingsupporting

confidence: 56%

“…Default parameters were used unless otherwise noted. The molecular modeling methods employed here are analogous to those previously published (see Wu, et al, [9] Vardy, et al [28] and references within).…”

Section: 32mentioning

confidence: 99%

Michael Acceptor Approach to the Design of New Salvinorin A- Based High Affinity Ligands to the Kappa-Opioid Receptor

Polepally¹,

Setola²,

Vardy³

et al. 2012

Planta Med

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“…It is interesting to note that most κOR ligands, particularly Sal A, exhibit nanomolar affinity for κOR. Interestingly, docking studies using the crystal structure of hκOR bound to the antagonist JDTic suggest that different chemotypes of κOR ligands bind to the same pocket in the receptor (25). We find that epimerization of Colly at C9 reduces agonist binding and signaling.…”

Section: Discussionmentioning

confidence: 73%

Collybolide is a novel biased agonist of κ-opioid receptors with potent antipruritic activity

Gupta

Gomes

Bobeck

et al. 2016

Proc. Natl. Acad. Sci. U.S.A.

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Among the opioid receptors, the κ-opioid receptor (κOR) has been gaining considerable attention as a potential therapeutic target for the treatment of complex CNS disorders including depression, visceral pain, and cocaine addiction. With an interest in discovering novel ligands targeting κOR, we searched natural products for unusual scaffolds and identified collybolide (Colly), a nonnitrogenous sesquiterpene from the mushroom Collybia maculata. This compound has a furyl-δ-lactone core similar to that of Salvinorin A (Sal A), another natural product from the plant Salvia divinorum. Characterization of the molecular pharmacological properties reveals that Colly, like Sal A, is a highly potent and selective κOR agonist. However, the two compounds differ in certain signaling and behavioral properties. Colly exhibits 10-to 50-fold higher potency in activating the mitogen-activated protein kinase pathway compared with Sal A. Taken with the fact that the two compounds are equipotent for inhibiting adenylyl cyclase activity, these results suggest that Colly behaves as a biased agonist of κOR. Behavioral studies also support the biased agonistic activity of Colly in that it exhibits ∼10-fold higher potency in blocking non-histamine-mediated itch compared with Sal A, and this difference is not seen in pain attenuation by these two compounds. These results represent a rare example of functional selectivity by two natural products that act on the same receptor. The biased agonistic activity, along with an easily modifiable structure compared with Sal A, makes Colly an ideal candidate for the development of novel therapeutics targeting κOR with reduced side effects.G-protein-coupled receptors | natural compounds | salvinorin A | dynorphin | antinociception

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“…To investigate the role of the vicinal C-terminal cysteine moiety, we introduced a number of eight-membered ring mimetics (Figure 4). Replacement of cysteine by homocysteine either individually or together yielded analogues with extended ring sizes (49,50) resulting in a significant loss of KOR affinity. Replacement of the disulfide bond by a diseleno bond (35 → 52) or a sulfurseleno bond (26 → 53) was possible without loss of affinity, but no metabolic stability improvement was observed.…”

Section: Journal Of Medicinal Chemistrymentioning

confidence: 99%

“…48 The recent X-ray structure of KOR in complex with an antagonist (JDTic; (3R)-7-hydroxy-N-[(2S)-1-[(3R,4R)-4-(3-hydroxyphenyl)-3,4-dimethylpiperidin-1-yl]-3-methylbutan-2-yl]-1,2,3,4-tetrahydroisoquinoline-3-carboxamide) 49 has been used to confirm earlier docking results and is supported by receptor mutagenesis and functional studies. 50 The consensus view is that the YGGF message domain interacts with KOR in a similar way as the antagonist JDTic, encompassing a conserved opioid receptor hydrophobic pocket comprising W124 (ECL1) , V134 (3.28) , I135 (3.19) , and C210 (ECL2) . Additionally the D138 (3.32) carboxylate interaction with the Y1-amine residue is also critical for high affinity interactions.…”

Section: ■ Introductionmentioning

confidence: 99%

Conopeptide-Derived κ-Opioid Agonists (Conorphins): Potent, Selective, and Metabolic Stable Dynorphin A Mimetics with Antinociceptive Properties

et al. 2016

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Opioid receptor screening of a conopeptide library led to a novel selective κ-opioid agonist peptide (conorphin T). Intensive medicinal chemistry, guided by potency, selectivity, and stability assays generated a pharmacophore model supporting rational design of highly potent and selective κ-opioid receptor (KOR) agonists (conorphins) with exceptional plasma stability. Conorphins are defined by a hydrophobic benzoprolyl moiety, a double arginine sequence, a spacer amino acid followed by a hydrophobic residue and a C-terminal vicinal disulfide moiety. The pharmacophore model was supported by computational docking studies, revealing receptor−ligand interactions similar to KOR agonist dynorphin A (1−8). A conorphin agonist inhibited colonic nociceptors in a mouse tissue model of chronic visceral hypersensitivity, suggesting the potential of KOR agonists for the treatment of chronic abdominal pain. This new conorphine KOR agonist class and pharmacophore model provide opportunities for future rational drug development and probes for exploring the role of the κ-opioid receptor.

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Chemotype-selective Modes of Action of κ-Opioid Receptor Agonists

Cited by 62 publications

References 44 publications

Michael Acceptor Approach to the Design of New Salvinorin A- Based High Affinity Ligands to the Kappa-Opioid Receptor

Michael Acceptor Approach to the Design of New Salvinorin A- Based High Affinity Ligands to the Kappa-Opioid Receptor

Collybolide is a novel biased agonist of κ-opioid receptors with potent antipruritic activity

Conopeptide-Derived κ-Opioid Agonists (Conorphins): Potent, Selective, and Metabolic Stable Dynorphin A Mimetics with Antinociceptive Properties

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