Figure 3 - available via license: Creative Commons Attribution 4.0 International
Content may be subject to copyright.
Source publication
Among the opioid receptors, the kappa opioid receptor (KOR) has been gaining substantial attention as a promising molecular target for the treatment of numerous human disorders, including pain, pruritus, affective disorders (i.e., depression and anxiety), drug addiction, and neurological diseases (i.e., epilepsy). Particularly, the knowledge that a...
Similar publications
Opioid addiction and the opioid overdose epidemic are becoming more serious, and the development of therapeutic agents is essential for the pharmacological treatment of substance use disorders. The κ-opioid receptor (KOP) is a member of the opioid receptor system that has been gaining attention as a promising molecular target for the treatment of n...
Citations
... Research on the physiologic role of DORs remains largely preclinical but may involve both nociceptive signaling and mood modulation [33,87,88]. Similarly, research on the KOR is primarily preclinical; evidence suggests that KOR antagonists may be helpful in both affective and addiction disorders [89]. Activity at the OLR-1 is discussed below. ...
Buprenorphine has become an important medication in the context of the ongoing opioid epidemic. However, complex pharmacologic properties and varying government regulations create barriers to its use. This narrative review is intended to facilitate buprenorphine use—including non-traditional initiation methods—by providers ranging from primary care providers to addiction specialists. This article briefly discusses the opioid epidemic and the diagnosis and treatment of opioid use disorder (OUD). We then describe the basic and complex pharmacologic properties of buprenorphine, linking these properties to their clinical implications. We guide readers through the process of initiating buprenorphine in patients using full agonist opioids. As there is no single recommended approach for buprenorphine initiation, we discuss the details, advantages, and disadvantages of the standard, low-dose, bridging-strategy, and naloxone-facilitated initiation techniques. We consider the pharmacology of, and evidence base for, buprenorphine in the treatment of pain, in both OUD and non-OUD patients. Throughout, we address the use of buprenorphine in children and adolescent patients, and we finish with considerations related to the settings of pregnancy and breastfeeding.
... 8−10 K-opioid receptor (KOR) agonists have been shown to produce pain relief and can reduce drug-seeking; however, they can also provoke dysphoria and sedation. 11,12 A full/partial MOR agonist with KOR agonist activity (e.g., pentazocine, nalbuphine, and butorphanol) shows a decreased abuse liability, even though some patients have reported dysphoria and withdrawal was detected in opioid-addicted patients. 13 The development of a partial KOR agonist endowed with MOR activity could be a valuable alternative to reach non-addictive analgesic activity without dysphoria, aiming to mitigate and titrate rewarding versus dysphoric behavior of the compound. ...
The discovery of efficacious and safe analgesics with reduced side effects is the foremost challenge in the pain field. In this work, we report the in vitro and in vivo evaluation of linear and cyclic analogues of biphalin with the aim to complete the series of structural modifications previously applied in the development of opioid peptides incorporating a xylene bridge. Replacement of Tyr 1,1 ′ by Dmt (2,5-dimethyltyrosine) in the linear biphalin analogue AM94 and cyclic analogue MACE4 resulted in two new compounds (namely, MJ2 and MJ5) endowed with improved KOR/ MOR/DOR binding affinity. Both compounds showed a strong antinociceptive profile in in vivo models of nociception, allodynia, and hyperalgesia via the tail flick, hot plate, and formalin tests after intracerebroventricular and subcutaneous administration. One of these ligands, MJ2, was also tested in tolerance and dependence studies, exhibiting very little withdrawal symptoms.
... The first strategy was the extension of the N-alkyl substituent. In vitro binding studies showed good KOR affinity and potency, but weak selectivity with a decreasing trend as the number of carbons increased [27]. ...
The κ-opioid receptor (KOR) has recently emerged as an alternative therapeutic target for the development of pain medications, without deleterious side effects associated with the μ-opioid receptor (MOR). However, modulation of KOR is currently under investigation for the treatment of depression, mood disorders, psychiatric comorbidity, and specific drug addictions. However, KOR agonists also trigger adverse effects including sedation, dysphoria, and hallucinations. In this respect, there is currently much debate on alternative paradigms. Recent effort has been devoted in search of biased ligands capable of selectively activating favorable signaling over signaling associated with unwanted side effects. On the other hand, the use of partial agonists is expected to allow the analgesia to be produced at dosages lower than those required to produce the adverse effects. More empirically, the unwanted central effects can be also avoided by using peripherally restricted agonists. In this review, we discuss the more recent trends in the design of KOR-selective, biased or partial, and finally, peripherally acting agonists. Special emphasis is given on the discussion of the most recent approaches for controlling functional selectivity of KOR-specific ligands.
... The Kappa Opioid Receptor is one of four opioid receptors that belong to the G-protein-coupled receptors (GPCR) superfamily. Research on opioid receptors, particularly on KOR, has been gaining momentum as it mediates affective disorders such as depression and anxiety, neurological diseases like epilepsy, but also pain and drug addiction, making it a promising pharmacological target [37][38][39][40]. The ADORA2A is also a part of the GPCR superfamily and mediates pain, motor control, and mood [40]. ...
Drug design is an important area of study for pharmaceutical businesses. However, low efficacy, off-target delivery, time consumption, and high cost are challenges and can create barriers that impact this process. Deep Learning models are emerging as a promising solution to perform de novo drug design, i.e., to generate drug-like molecules tailored to specific needs. However, stereochemistry was not explicitly considered in the generated molecules, which is inevitable in targeted-oriented molecules. This paper proposes a framework based on Feedback Generative Adversarial Network (GAN) that includes optimization strategy by incorporating Encoder–Decoder, GAN, and Predictor deep models interconnected with a feedback loop. The Encoder–Decoder converts the string notations of molecules into latent space vectors, effectively creating a new type of molecular representation. At the same time, the GAN can learn and replicate the training data distribution and, therefore, generate new compounds. The feedback loop is designed to incorporate and evaluate the generated molecules according to the multiobjective desired property at every epoch of training to ensure a steady shift of the generated distribution towards the space of the targeted properties. Moreover, to develop a more precise set of molecules, we also incorporate a multiobjective optimization selection technique based on a non-dominated sorting genetic algorithm. The results demonstrate that the proposed framework can generate realistic, novel molecules that span the chemical space. The proposed Encoder–Decoder model correctly reconstructs 99% of the datasets, including stereochemical information. The model’s ability to find uncharted regions of the chemical space was successfully shown by optimizing the unbiased GAN to generate molecules with a high binding affinity to the Kappa Opioid and Adenosine A2a\documentclass[12pt]{minimal} \usepackage{amsmath} \usepackage{wasysym} \usepackage{amsfonts} \usepackage{amssymb} \usepackage{amsbsy} \usepackage{mathrsfs} \usepackage{upgreek} \setlength{\oddsidemargin}{-69pt} \begin{document}$$A_ {2a}$$\end{document} receptor. Furthermore, the generated compounds exhibit high internal and external diversity levels 0.88 and 0.94, respectively, and uniqueness.
... 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]. ...
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.
... The Kappa Opioid Receptor is one of four opioid receptors that belong to the G-protein-coupled receptors (GPCR) superfamily. Research on opioid receptors, particularly on KOR, has been gaining momentum as it mediates affective disorders such as depression and anxiety, neurological diseases like epilepsy, but also pain and drug addiction, making it a promising pharmacological target [27,28,29,30]. The ADORA2A is also a part of the GPCR superfamily and mediates pain, motor control, and mood [31]. ...
Drug design is an important area of study for pharmaceutical businesses. However, low efficacy, off-target delivery, time consumption, and high cost are challenges and can create barriers that impact this process. Deep Learning models are emerging as a promising solution to perform de novo drug design, i.e., to generate drug-like molecules tailored to specific needs. However, stereochemistry was not explicitly considered in the generated molecules, which is inevitable in targeted-oriented molecules. This paper proposes a framework based on Feedback Generative Adversarial Network (GAN) that includes optimization strategy by incorporating Encoder-Decoder, GAN, and Predictor deep models interconnected with a feedback loop. The Encoder-Decoder converts the string notations of molecules into latent space vectors, effectively creating a new type of molecular representation. At the same time, the GAN can learn and replicate the training data distribution and, therefore, generate new compounds. The feedback loop is designed to incorporate and evaluate the generated molecules according to the desired property at every epoch of training to ensure a steady shift of the generated distribution towards the space of the targeted property. The results demonstrate that the proposed framework can generate realistic, novel molecules that span the chemical space. The proposed Encoder-Decoder model correctly reconstructs 99% of the datasets, including stereochemical information. The model's ability to find uncharted regions of the chemical space was successfully shown by optimizing the unbiased GAN to generate molecules with a high binding affinity to the Kappa Opioid and Adenosine A2a Receptor. Furthermore, the generated compounds exhibit high internal and external diversity levels 0.88 and 0.94, respectively, and uniqueness.
... Therefore, when treating patients with cancer, the dosage and treatment duration of opioids should be weighed (186,190). To design opioid analgesics without side effects, it is important to understand the molecular mechanisms, signaling pathways and effects of KOR in combination with chemotherapeutic drugs (191). For example, by decreasing entry of opioids into the central nervous system, selective targeting of KOR to the peripheral nervous system and inflammatory tissues is biased towards activation of analgesia-associated intracellular signaling pathways. ...
The κ‑opioid receptor (KOR) is one of the primary receptors of opioids and serves a vital role in the regulation of pain, anesthesia, addiction and other pathological and physiological processes. KOR is associated with several types of cancer and may influence cancer progression. It has been proposed that KOR may represent a new tumor molecular marker and provide a novel basis for molecular targeted therapies for cancer. However, the association between KOR and cancer remains to be explored comprehensively. The present review introduces KOR and its association with different types of cancer. Improved understanding of KOR may facilitate development of novel antitumor therapies.
... With the awareness that narcotic addiction is derived from the MOR, the KOR is emerging as a promising target for developing safer therapeutics without the common side effects associated with classical opioids, such as rewarding effects, respiratory depression and overdose. Schmidhammer et al. [12] reviewed recent chemical developments of SARs on diphenethylamines, a new class of structurally distinct and selective KOR ligands, with diverse profiles ranging from potent and selective agonists to G protein-biased agonists and selective antagonists. The first lead molecules in the series included the selective KOR full agonist HS665 and the partial agonist HS666. ...
... They reported on opioid agonist/NK1 antagonist Tyr-[D-Lys-Phe-Phe-Asp]-Asn-D-Trp-Phe-D-Trp-Leu-Nle-NH 2 and opioid agonist/NK1 agonist Tyr-[D-Lys-Phe-Phe-Asp]-Gln-Phe-Phe-Gly-Leu-Met-NH 2 peptide hybrids with antinociceptive efficacy without inducing analgesic tolerance or constipation in mice after intraperitoneal administration. Research approaches to diminish opioid liabilities take advantage of the current concept of functional selectivity, with biased ligands (agonists and antagonists) as innovative opportunities for opioid pain therapy and use management, subjects reviewed in [12,[15][16][17] and explored in a research article [18]. ...
The interest in opioids such as morphine, the prototypical opioid ligand, has been maintained throughout the years [...]
This paper is the forty-third consecutive installment of the annual anthological review of research concerning the endogenous opioid system, summarizing articles published during 2020 that studied the behavioral effects of molecular, pharmacological and genetic manipulation of opioid peptides and receptors as well as effects of opioid/opiate agonists and antagonists. The review is subdivided into the following specific topics: molecular-biochemical effects and neurochemical localization studies of endogenous opioids and their receptors (1), the roles of these opioid peptides and receptors in pain and analgesia in animals (2) and humans (3), opioid-sensitive and opioid-insensitive effects of nonopioid analgesics (4), opioid peptide and receptor involvement in tolerance and dependence (5), stress and social status (6), learning and memory (7), eating and drinking (8), drug abuse and alcohol (9), sexual activity and hormones, pregnancy, development and endocrinology (10), mental illness and mood (11), seizures and neurologic disorders (12), electrical-related activity and neurophysiology (13), general activity and locomotion (14), gastrointestinal, renal and hepatic functions (15), cardiovascular responses (16), respiration and thermoregulation (17), and immunological responses (18).
Introduction:
Neuroactive peptides are peptides produced by neurons and released through controlled mechanisms that bind to specific receptors on nerve, glial, or other cell types, causing biochemical response(s) within these cells.
Areas covered:
This article summarizes and interprets recent advancements in our knowledge of neuroactive peptides with pro- or anti-convulsant action, and about new drugs that use the molecular machinery of neuroactive peptides to suppress seizures.
Expert opinion:
According to the results of preclinical and limited clinical investigations to date, the highest potential to become anti-epileptic drugs with marketing authorization belongs to non-peptide agonists of melanocortin receptors, thyrotropin-releasing hormone receptors, ghrelin receptors, galanin receptors, somatostatin and cortistatin receptors, oxytocin receptors, cholecystokinin receptors, and opioid kappa receptors, followed by non-peptide antagonists of the renin-angiotensin system, corticotropin-releasing hormone receptors, NK1 receptors for substance P, arginine-vasopressin receptors, and opioid delta receptors.
