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Dual-Target Mopr/Dopr Ligands As Drug Candidates for Persistent Pain Relief

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Dual-Target Mopr/Dopr Ligands As Drug Candidates for Persistent Pain Relief molecules Review LP1 and LP2: Dual-Target MOPr/DOPr Ligands as Drug Candidates for Persistent Pain Relief Lorella Pasquinucci 1,* , Carmela Parenti 2, Zafiroula Georgoussi 3, Lorena Reina 4, Emilia Tomarchio 5 and Rita Turnaturi 1,* 1 Department of Drug and Health Sciences, Medicinal Chemistry Section, University of Catania, Viale A. Doria 6, 95125 Catania, Italy 2 Department of Drug and Health Sciences, Pharmacology and Toxicology Section, University of Catania, Viale A. Doria 6, 95125 Catania, Italy; [email protected] 3 Laboratory of Cellular Signaling and Molecular Pharmacology, Institute of Biosciences and Applications, National Centre for Scientific Research “Demokritos” Ag. Paraskevi-Attikis, 15310 Athens, Greece; [email protected] 4 Postgraduate School of Clinical Pharmacology, Toxicology University of Catania, via S. Sofia n. 97, 95100 Catania, Italy; [email protected] 5 Postgraduate School of Anesthesiology and Intensive Care, University of Milan, Via Francesco Sforza, 35, 20122 Milan, Italy; [email protected] * Correspondence: [email protected] (L.P.); [email protected] (R.T.); Tel.: +39-095-738-4273 (L.P. & R.T.) Abstract: Although persistent pain is estimated to affect about 20% of the adult population, current treatments have poor results. Polypharmacology, which is the administration of more than one drug targeting on two or more different sites of action, represents a prominent therapeutic approach for the clinical management of persistent pain. Thus, in the drug discovery process the “one-molecule- multiple targets” strategy nowadays is highly recognized. Indeed, multitarget ligands displaying a Citation: Pasquinucci, L.; Parenti, C.; better antinociceptive activity with fewer side effects, combined with favorable pharmacokinetic and Georgoussi, Z.; Reina, L.; Tomarchio, pharmacodynamic characteristics, have already been shown. Multitarget ligands possessing non- E.; Turnaturi, R. LP1 and LP2: Dual-Target MOPr/DOPr Ligands as opioid/opioid and opioid/opioid mechanisms of action are considered as potential drug candidates Drug Candidates for Persistent Pain for the management of various pain conditions. In particular, dual-target MOPr (mu opioid peptide Relief. Molecules 2021, 26, 4168. receptor)/DOPr (delta opioid peptide receptor) ligands exhibit an improved antinociceptive profile https://doi.org/10.3390/ associated with a reduced tolerance-inducing capability. The benzomorphan-based compounds LP1 molecules26144168 and LP2 belong to this class of dual-target MOPr/DOPr ligands. In the present manuscript, the structure–activity relationships and the pharmacological fingerprint of LP1 and LP2 compounds as Academic Editor: Laura Micheli suitable drug candidates for persistent pain relief is described. Received: 29 May 2021 Keywords: benzomorphan; mu opioid receptor; delta opioid receptor; multitarget ligands; biased Accepted: 6 July 2021 agonism; pain Published: 8 July 2021 Publisher’s Note: MDPI stays neutral with regard to jurisdictional claims in 1. Introduction published maps and institutional affil- iations. In pain transmission the multitude and complexity of involved neuronal mechanisms provide several possible targets for pharmacological intervention [1]. Thus, different antinociceptive drugs with distinct mechanisms and sites of action can provide pain relief. For instance, nonsteroidal anti-inflammatory drugs (NSAIDs) are recommended for acute and chronic musculoskeletal and post-surgical pain management [2,3]. Neuropathic Copyright: © 2021 by the authors. Licensee MDPI, Basel, Switzerland. pain and post-herpetic neuralgia (PHN) relief may be evoked with local anesthetics such α δ This article is an open access article as the well-known lidocaine patch [4,5]. Additionally, ligands acting on the 2- subunit of distributed under the terms and voltage dependent calcium channels are often used in the management of neuropathic pain, conditions of the Creative Commons such as diabetic neuropathy and PHN [6,7]. Other analgesic/adjuvant agents used to treat Attribution (CC BY) license (https:// persistent pain states are represented by monoamine reuptake inhibitors such as TCAs (e.g., creativecommons.org/licenses/by/ amitriptyline, clomipramine, desipramine and imipramine), and serotonin-noradrenaline 4.0/). Molecules 2021, 26, 4168. https://doi.org/10.3390/molecules26144168 https://www.mdpi.com/journal/molecules Molecules 2021, 26, x FOR PEER REVIEW 2 of 17 Molecules 2021, 26, 4168 2 of 17 TCAs (e.g., amitriptyline, clomipramine, desipramine and imipramine), and serotonin- reuptakenoradrenaline inhibitors reuptake (SNRIs) inhibitors (e.g., duloxetine, (SNRIs) (e.g., milnacipran duloxetine, and milnacipran venlafaxine) and [ 8venlafaxine)–10]. How- ever,[8–10]. opioid However, analgesics opioid continue analgesics to becontinue first-line to agentsbe first-line for the agents relief for of acutethe relief nociceptive of acute painnociceptive and chronic pain and cancer chronic pain, cancer and most pain, of and them most are of MOPr them (muare MOPr opioid (mu peptide opioid receptor) peptide agonists,receptor) suchagonists, as morphine such as morphine (Figure1)[ (Figure11]. 1) [11]. FigureFigure 1.1. StructuresStructures ofof morphine,morphine, DPI-3290DPI-3290 andand UMBUMB 425.425. AlthoughAlthough MOPrMOPr agonistsagonists representrepresent thethe firstfirst treatmenttreatment optionoption forfor nociceptivenociceptive painpain management,management, theirtheir useuse inin long-termlong-term treatmenttreatment ofof persistentpersistent painpain statesstates isis limitedlimited byby sideside effectseffects [[12,13].12,13]. ItIt hashas beenbeen provedproved thatthat antinociceptionantinociception andand sideside effectseffects areare bothboth elicitedelicited byby MOPrMOPr activation.activation. BuildingBuilding uponupon thesethese observationsobservations andand consideringconsidering thatthat aa single-targetsingle-target antinociceptiveantinociceptive agentagent maymay notnot provideprovide optimaloptimal antinociception,antinociception, multidrugmultidrug analgesicanalgesic ap-ap- proachesproaches or or polypharmacology polypharmacology have have been been introduced introduced into into clinical clinical practice practice for thefor treatment the treat- ofment both of acute both andacute persistent and persistent pain [pain14]. Various[14]. Various clinical clinical trials, trials, performed performed on patients on patients that underwent minor surgery, revealed additive or synergistic analgesic effects by the combi- that underwent minor surgery, revealed additive or synergistic analgesic effects by the nation of NSAIDs with systemic opioids [15], revealing the ability of NSAIDs to reduce combination of NSAIDs with systemic opioids [15], revealing the ability of NSAIDs to the dose of opioids, with subsequent reduction of opioid-induced side effects. Similarly, reduce the dose of opioids, with subsequent reduction of opioid-induced side effects. Sim- in patients with persistent pain conditions such as neuropathic pain and PHN, an im- ilarly, in patients with persistent pain conditions such as neuropathic pain and PHN, an proved analgesic efficacy was reported for a multidrug regimen consisting of morphine improved analgesic efficacy was reported for a multidrug regimen consisting of morphine or oxycodone with pregabalin [16], gabapentin with nortriptyline [17]. Moreover, the or oxycodone with pregabalin [16], gabapentin with nortriptyline [17]. Moreover, the co- co-administration of two opioid drugs improved the analgesia MOPr-elicited by reducing administration of two opioid drugs improved the analgesia MOPr-elicited by reducing the incidence of side effects [18,19]. The co-administration of oxycodone and low-dose the incidence of side effects [18,19]. The co-administration of oxycodone and low-dose naloxone (a non-selective opioid antagonist) decreased the development of constipation naloxone (a non-selective opioid antagonist) decreased the development of constipation while maintaining a valuable analgesic effect, thus improving the safety and tolerability ofwhile the treatmentmaintaining [20 a,21 valuable]. However, analgesic a polypharmacology effect, thus improving approach the providessafety and risks tolerability related toof differentthe treatment pharmacokinetic/pharmacodynamic [20,21]. However, a polypharmacology relationships approach between provides co-administered risks related drugsto different that could pharmacokinetic/pharmacodyna lead to unpredictable biologicalmic variabilityrelationships [22, 23between]. co-administered drugsIn that this could perspective lead to the unpredictable past medicinal biological chemistry variability paradigm [22,23]. “one-target, one-disease” has beenIn this reconverted perspective into the “one-molecule, past medicinal multiplechemistry targets” paradigm through “one-target, the development one-disease” of multitargethas been reconverted ligands [24 ,into25]. Multitarget“one-molecule, ligand—a multiple single targets” antinociceptive through the drug development able to act on of differentmultitarget receptor ligands sites, [24,25]. also withMultitarget different ligand—a mechanisms single of antinociceptive action—could represent drug able a validto act approachon different for painreceptor management. sites, also Inwith comparison different with mechanisms the multidrug of action—could therapy approach, represent these a compoundsvalid approach display for morepain predictablemanagement. pharmacokinetic In comparison and
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