Kappa Opioid Receptor Ligands and Pharmacology: Diphenethylamines, a Class of Structurally Distinct, Selective Kappa Opioid Ligands

Spetea, Mariana; Schmidhammer, Helmut

doi:10.1007/164_2020_431

Cited by 6 publications

(10 citation statements)

References 146 publications

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“…Indeed, the activation of DYN/KOR system is crucial during stress responses, and either traumatic stress or addiction development increases its function ( Van’t Veer and Carlezon, 2013 ; Karkhanis et al, 2017 ), leading to increased risk of SUD in patients that lived traumatic events. Alternatively, a KOR biased-agonist, averting the β-arrestin 2-related signalling mediating dysphoria would be advantageous compared to MOR agonists for pain management and/or prevention of PTSD development, as such agonist could prevent dependency ( Spetea and Schmidhammer, 2022 ). Nevertheless, future pharmacological studies should better explore gender effects for these KOR ligands, since agonists have good analgesics properties but inconsistent dysphoric side effects in women ( Chartoff and Mavrikaki, 2015 ).…”

Section: Discussionmentioning

confidence: 99%

“…KOR activate the HPA axis ( Van’t Veer and Carlezon, 2013 ) and DYN is often co-expressed with CRF in regions such as the CeA and the PVN ( Crowley and Kash, 2015 ). In view of these observations, the therapeutic-like action of KOR antagonists, in animal models of anxiety as well as in models commonly used to screen antidepressant drugs, is not surprising ( Spetea and Schmidhammer, 2022 ). Furthermore, although controversial at this point, KOR antagonists may effectively reduce associative fear memories, by acting on some structures involved in traumatic fear memory formation ( Daumas et al, 2007 ; Cole et al, 2011 ; Knoll et al, 2011 ).…”

Section: Discussionmentioning

confidence: 99%

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Traumatic Stress-Induced Vulnerability to Addiction: Critical Role of the Dynorphin/Kappa Opioid Receptor System

2022

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Substance use disorders (SUD) may emerge from an individual’s attempt to limit negative affective states and symptoms linked to stress. Indeed, SUD is highly comorbid with chronic stress, traumatic stress, or post-traumatic stress disorder (PTSD), and treatments approved for each pathology individually often failed to have a therapeutic efficiency in such comorbid patients. The kappa-opioid receptor (KOR) and its endogenous ligand dynorphin (DYN), seem to play a key role in the occurrence of this comorbidity. The DYN/KOR function is increased either in traumatic stress or during drug use, dependence acquisition and DYN is released during stress. The behavioural effects of stress related to the DYN/KOR system include anxiety, dissociative and depressive symptoms, as well as increased conditioned fear response. Furthermore, the DYN/KOR system is implicated in negative reinforcement after the euphoric effects of a drug of abuse ends. During chronic drug consumption DYN/KOR functions increase and facilitate tolerance and dependence. The drug-seeking behaviour induced by KOR activation can be retrieved either during the development of an addictive behaviour, or during relapse after withdrawal. DYN is known to be one of the most powerful negative modulators of dopamine signalling, notably in brain structures implicated in both reward and fear circuitries. KOR are also acting as inhibitory heteroreceptors on serotonin neurons. Moreover, the DYN/KOR system cross-regulate with corticotropin-releasing factor in the brain. The sexual dimorphism of the DYN/KOR system could be the cause of the gender differences observed in patients with SUD or/and traumatic stress-related pathologies. This review underlies experimental and clinical results emphasizing the DYN/KOR system as common mechanisms shared by SUD or/and traumatic stress-related pathologies, and suggests KOR antagonist as a new pharmacological strategy to treat this comorbidity.

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Section: Discussionmentioning

confidence: 99%

Section: Discussionmentioning

confidence: 99%

Traumatic Stress-Induced Vulnerability to Addiction: Critical Role of the Dynorphin/Kappa Opioid Receptor System

2022

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“…Therefore, the KOR has recently gained increased attention as a prominent GPCR in the pursuit of novel pharmacotherapies for a variety of human diseases, due to its role in mediating many physiological and pathophysiological responses [15]. Activation of the KOR is viewed as a promising strategy for the treatment of pain, itch and epilepsy, whereas receptor blockade is associated with potential therapeutic effects in mood (depression and anxiety) and addictive disorders [16][17][18][19][20][21]. Selective ligands for the KOR with diverse scaffolds-such as small molecules and peptides, natural products and synthetic molecules-and distinct pharmacology were designed [19][20][21][22][23][24].…”

Section: Introductionmentioning

confidence: 99%

“…Activation of the KOR is viewed as a promising strategy for the treatment of pain, itch and epilepsy, whereas receptor blockade is associated with potential therapeutic effects in mood (depression and anxiety) and addictive disorders [16][17][18][19][20][21]. Selective ligands for the KOR with diverse scaffolds-such as small molecules and peptides, natural products and synthetic molecules-and distinct pharmacology were designed [19][20][21][22][23][24]. Although targeting the KOR in drug discovery is very promising, the KOR is not devoid of detrimental side effects with receptor activation causing diuresis, dysphoria, sedation, psychotomimesis and anxiety in humans [15][16][17].…”

Section: Introductionmentioning

confidence: 99%

“…In addition, pain is a key clinical indication for KOR agonists, with experimental and clinical evidence that the KOR modulates pain processing in the CNS and PNS without the risk of physical dependence or abuse liability of MOR agonists [30][31][32][33]. Initially, KOR antagonists were widely used as pharmacological tools for studying the in vitro and in vivo actions upon KOR stimulation [19][20][21]28,34] The first selective KOR antagonists included ligands with a morphinan scaffold structure, i.e., nor-binaltorphimine (nor-BNI) [35], 5 -guanidinonaltrindole (5 -GNTI) [36] and the 4 -phenylpiperidine derivative, JDTic [37] (Figure 1). Preclinical studies showed that KOR inhibition or receptor depletion in the brain resulted in attenuation of depressive, anxiogenic affective and addictive-like behaviors, thus encouraging the development of selective KOR antagonists for the treatment of mood and addictive disorders.…”

Section: Introductionmentioning

confidence: 99%

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In Vitro, In Vivo and In Silico Characterization of a Novel Kappa-Opioid Receptor Antagonist

et al. 2022

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Kappa-opioid receptor (KOR) antagonists are promising innovative therapeutics for the treatment of the central nervous system (CNS) disorders. The new scaffold opioid ligand, Compound A, was originally found as a mu-opioid receptor (MOR) antagonist but its binding/selectivity and activation profile at the KOR and delta-opioid receptor (DOR) remain elusive. In this study, we present an in vitro, in vivo and in silico characterization of Compound A by revealing this ligand as a KOR antagonist in vitro and in vivo. In the radioligand competitive binding assay, Compound A bound at the human KOR, albeit with moderate affinity, but with increased affinity than to the human MOR and without specific binding at the human DOR, thus displaying a preferential KOR selectivity profile. Following subcutaneous administration in mice, Compound A effectively reverse the antinociceptive effects of the prototypical KOR agonist, U50,488. In silico investigations were carried out to assess the structural determinants responsible for opioid receptor subtype selectivity of Compound A. Molecular docking, molecular dynamics simulations and dynamic pharmacophore (dynophore) generation revealed differences in the stabilization of the chlorophenyl moiety of Compound A within the opioid receptor binding pockets, rationalizing the experimentally determined binding affinity values. This new chemotype bears the potential for favorable ADMET properties and holds promise for chemical optimization toward the development of potential therapeutics.

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Discovery of Novel, Selective, and Nonbasic Agonists for the Kappa-Opioid Receptor Determined by Salvinorin A-Based Virtual Screening

Puls,

Olivé-Marti,

Hongnak

et al. 2024

J. Med. Chem.

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Modulating the kappa-opioid receptor (KOR) is a promising strategy for treating various human diseases. KOR agonists show potential for treating pain, pruritus, and epilepsy, while KOR antagonists show potential for treating depression, anxiety, and addiction. The diterpenoid Salvinorin A (SalA), a secondary metabolite of Salvia divinorum, is a potent and selective KOR agonist. Unlike typical opioids, SalA lacks a basic nitrogen, which encouraged us to search for nonbasic KOR ligands. Through structure-based virtual screening using 3D pharmacophore models based on the binding mode of SalA, we identified novel, nonbasic, potent, and selective KOR agonists. In vitro studies confirmed two virtual hits, SalA-VS-07 and SalA-VS-08, as highly selective for the KOR and showing G protein-biased KOR agonist activity. Both KOR ligands share a novel spiro-moiety and a nonbasic scaffold. Our findings provide novel starting points for developing therapeutics aimed at treating pain and other conditions in which KOR is a central player.

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Kappa Opioid Receptor Ligands and Pharmacology: Diphenethylamines, a Class of Structurally Distinct, Selective Kappa Opioid Ligands

Cited by 6 publications

References 146 publications

Traumatic Stress-Induced Vulnerability to Addiction: Critical Role of the Dynorphin/Kappa Opioid Receptor System

Traumatic Stress-Induced Vulnerability to Addiction: Critical Role of the Dynorphin/Kappa Opioid Receptor System

In Vitro, In Vivo and In Silico Characterization of a Novel Kappa-Opioid Receptor Antagonist

Discovery of Novel, Selective, and Nonbasic Agonists for the Kappa-Opioid Receptor Determined by Salvinorin A-Based Virtual Screening

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