Mechanistic Characterization of the Pharmacological Profile of HS-731, a Peripherally Acting Opioid Analgesic, at the µ-, δ-, κ-Opioid and Nociceptin Receptors

Puls, Kristina; Schmidhammer, Helmut; Wolber, Gerhard; Spetea, Mariana

doi:10.3390/molecules27030919

Cited by 9 publications

(8 citation statements)

References 87 publications

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“…In order to account for the orientation of the non-conserved residues within the binding pocket, we superimposed the KOR-SalA complex according to its transmembrane region (OPM-Database entry: 6B73) with the active-state structures of MOR (PDB-ID: 5C1M [ 63 ]), DOR (PDB-ID: 6PT2 [ 64 ]) and NOP ( Figure 4 ). Since there is no experimentally derived active-state NOP structure available, we used a homology model based on the active-state KOR crystal structure (PDB-ID: 6B73 [ 22 ]) already described in one of our previous publications [ 65 ].…”

Section: Resultsmentioning

confidence: 99%

Solving an Old Puzzle: Elucidation and Evaluation of the Binding Mode of Salvinorin A at the Kappa Opioid Receptor

Puls

Wolber

2023

Molecules

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The natural product Salvinorin A (SalA) was the first nitrogen-lacking agonist discovered for the opioid receptors and exhibits high selectivity for the kappa opioid receptor (KOR) turning SalA into a promising analgesic to overcome the current opioid crisis. Since SalA’s suffers from poor pharmacokinetic properties, particularly the absence of gastrointestinal bioavailability, fast metabolic inactivation, and subsequent short duration of action, the rational design of new tailored analogs with improved clinical usability is highly desired. Despite being known for decades, the binding mode of SalA within the KOR remains elusive as several conflicting binding modes of SalA were proposed hindering the rational design of new analgesics. In this study, we rationally determined the binding mode of SalA to the active state KOR by in silico experiments (docking, molecular dynamics simulations, dynophores) in the context of all available mutagenesis studies and structure-activity relationship (SAR) data. To the best of our knowledge, this is the first comprehensive evaluation of SalA’s binding mode since the determination of the active state KOR crystal structure. SalA binds above the morphinan binding site with its furan pointing toward the intracellular core while the C2-acetoxy group is oriented toward the extracellular loop 2 (ECL2). SalA is solely stabilized within the binding pocket by hydrogen bonds (C210ECL2, Y3127.35, Y3137.36) and hydrophobic contacts (V1182.63, I1393.33, I2946.55, I3167.39). With the disruption of this interaction pattern or the establishment of additional interactions within the binding site, we were able to rationalize the experimental data for selected analogs. We surmise the C2-substituent interactions as important for SalA and its analogs to be experimentally active, albeit with moderate frequency within MD simulations of SalA. We further identified the non-conserved residues 2.63, 7.35, and 7.36 responsible for the KOR subtype selectivity of SalA. We are confident that the elucidation of the SalA binding mode will promote the understanding of KOR activation and facilitate the development of novel analgesics that are urgently needed.

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Section: Resultsmentioning

confidence: 99%

Solving an Old Puzzle: Elucidation and Evaluation of the Binding Mode of Salvinorin A at the Kappa Opioid Receptor

Puls

Wolber

2023

Molecules

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“…application, its significant and prolonged duration of antinociceptive action (up to 4 h) after oral administration to rats with carrageenan-induced inflammatory pain was notable [ 41 ]. Furthermore, a recent study described the lack of binding to the human NOP receptor of 3b (HS-731) [ 45 ].…”

Section: Peripheralization Strategies Applied To Morphinansmentioning

confidence: 99%

Peripheralization Strategies Applied to Morphinans and Implications for Improved Treatment of Pain

et al. 2023

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Opioids are considered the most effective analgesics for the treatment of moderate to severe acute and chronic pain. However, the inadequate benefit/risk ratio of currently available opioids, together with the current ‘opioid crisis’, warrant consideration on new opioid analgesic discovery strategies. Targeting peripheral opioid receptors as effective means of treating pain and avoiding the centrally mediated side effects represents a research area of substantial and continuous attention. Among clinically used analgesics, opioids from the class of morphinans (i.e., morphine and structurally related analogues) are of utmost clinical importance as analgesic drugs activating the mu-opioid receptor. In this review, we focus on peripheralization strategies applied to N-methylmorphinans to limit their ability to cross the blood–brain barrier, thus minimizing central exposure and the associated undesired side effects. Chemical modifications to the morphinan scaffold to increase hydrophilicity of known and new opioids, and nanocarrier-based approaches to selectively deliver opioids, such as morphine, to the peripheral tissue are discussed. The preclinical and clinical research activities have allowed for the characterization of a variety of compounds that show low central nervous system penetration, and therefore an improved side effect profile, yet maintaining the desired opioid-related antinociceptive activity. Such peripheral opioid analgesics may represent alternatives to presently available drugs for an efficient and safer pain therapy.

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“…In order to account for the orientation of the non-conserved residues within the binding pocket, we superimposed the KOR-SalA complex according its transmembrane region (OPM-Database entry: 6B73) with the active-state structures of MOR (PDB-ID: 5C1M [64]), DOR (PDB-ID: 6PT2 [65]) and NOP (Figure 4). Since there is no experimentally derived active-state NOP structure available, we used a homology model based on the active-state KOR crystal structure (PDB-ID: 6B73 [22]) already described in one of our previous publications [66]. V118 2.63 at the top of KOR-TM2 forms hydrophobic contacts with C19 (methyl moiety between Ring A and B) of SalA.…”

Section: Non-conserved Residues Harboring Salvinorin a At The Kappa O...mentioning

confidence: 99%

Solving an Old Puzzle: Elucidation and Evaluation of the Binding Mode of Salvinorin A at the Kappa Opioid Receptor

Puls¹,

Wolber²

2022

Preprint

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The natural product Salvinorin A (SalA) was the first nitrogen-lacking agonist discovered for the opioid receptors and exhibits high selectivity for the kappa opioid receptor (KOR) turning SalA into a promising analgesic to overcome the current opioid crisis. Since SalA’s suffers from poor pharmacokinetic properties, particularly the absence of gastrointestinal bioavailability, fast metabolic inactivation and subsequent short duration of action, the rational design of new tailored analogs with improved clinical usability is highly desired. Despite being known for decades, the binding mode of SalA within the KOR remains elusive as several conflicting binding modes of SalA were proposed hindering the rational design of new analgesics. In this study, we rationally determined the binding mode of SalA to the active state KOR by in silico experiments (docking, molecular dynamics simulations, dynophores) in the context of all available mutagenesis studies and structure-activity relationship (SAR) data. To the best of our knowledge this is the first comprehensive evaluation of SalA’s binding mode since the determination of the active state KOR crystal structure. SalA binds above the morphinan binding site with its furan pointing towards the intracellular core while the C2-acetoxy group is oriented towards the extracellular loop 2 (ECL2). SalA is solely stabilized within the binding pocket by hydrogen bonds (C210ECL2, Y3127.35, Y3137.36) and hydrophobic contacts (V1182.63, I1393.33, I2946.55, I3167.39). With the disruption of this interaction pattern or the establishment of additional interactions within the binding site we were able to rationalize the experimental data for selected analogs. We surmise the C2-substituent interactions as important for SalA and its analogs to be experimentally active, albeit moderate frequency within MD simulations of SalA. We further identified the non-conserved residues 2.63, 7.35, and 7.36 responsible for the KOR subtype selectivity of SalA. We are confident that the elucidation of the SalA binding mode will promote the understanding of KOR activation and the facilitate the development of novel analgesics that are urgently needed.

show abstract

Mechanistic Characterization of the Pharmacological Profile of HS-731, a Peripherally Acting Opioid Analgesic, at the µ-, δ-, κ-Opioid and Nociceptin Receptors

Cited by 9 publications

References 87 publications

Solving an Old Puzzle: Elucidation and Evaluation of the Binding Mode of Salvinorin A at the Kappa Opioid Receptor

Solving an Old Puzzle: Elucidation and Evaluation of the Binding Mode of Salvinorin A at the Kappa Opioid Receptor

Peripheralization Strategies Applied to Morphinans and Implications for Improved Treatment of Pain

Solving an Old Puzzle: Elucidation and Evaluation of the Binding Mode of Salvinorin A at the Kappa Opioid Receptor

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