Multitarget opioid ligands are potential drugs for the pain management on the basis of their low propensity to induce side effects, such as tolerance. Indeed, it has been proved that MOR/DOR agonist and MOR agonist/DOR antagonist ligands produce an enhanced antinociceptive effect coupled to a low incidence of undesirable effects usually limiting the long-term opioid use [1]. We previously described structure-activity relationships of a series of 5,9-dimethyl-2’-hydroxy-6,7-benzomorphan derivatives corroborating the criticality of the N-substituent nature. In that series of compounds the most promising was the 3-[(2R,6R,11R)-8-hydroxy-6,11-dimethyl-1,4,5,6-tetrahydro-2,6-methano-3-benzazocin-3(2H)-yl]-N-phenylpropanamide, named LP1, that was evaluated by in vitro and in vivo assays. The N-substituent nature conferred to LP1 affinity and intrinsic activity versus MOR and DOR, as detected by competition binding studies and functional in vitro assays. Moreover, in acute regimen, LP1, administered subcutaneously in male Sprague-Dawley rats, was as potent as morphine and its antinociceptive effect was completely naloxone-reversed [2]. Here, we evaluated whether the antinociceptive effect of LP1 was central or peripheral administering naloxone methiodide (NX-I) either intracerebroventricularly or subcutaneously. Moreover, using selective opioid antagonists for MOR, DOR and KOR naloxonazine (NLZ), naltrindole (NTI) and norBinaltorphimine (norBNI), respectively, we explored the opioid receptor subtypes involved in the antinociceptive effect of LP1. We also investigated LP1 effect on the antinociception DPDPE-induced to characterize its DOR profile better. In light of its MOR/DOR profile, we evaluated and compared the induction of tolerance to antinociceptive effects from treatment with LP1 and morphine. Data obtained by radiant tail flick test showed that LP1 acts prevalently in the central nervous system as a suitable MOR agonist able to counteract DPDPE analgesia. Moreover, unlike to morphine, LP1 showed a low capability to induce tolerance after chronic administration maintaining its antinociceptive effect until the ninth day [3]. Collected data described LP1 as a multitarget opioid ligand acting at the central level that is useful for the treatment of chronic pain.

THE BENZOMORPHAN-BASED COMPOUND LP1 AS A MULTITARGET OPIOID LIGAND FOR CHRONIC PAIN TREATMENT

PASQUINUCCI, Lorella Giuseppina;PARENTI, Carmela;TURNATURI, RITA;
2012

Abstract

Multitarget opioid ligands are potential drugs for the pain management on the basis of their low propensity to induce side effects, such as tolerance. Indeed, it has been proved that MOR/DOR agonist and MOR agonist/DOR antagonist ligands produce an enhanced antinociceptive effect coupled to a low incidence of undesirable effects usually limiting the long-term opioid use [1]. We previously described structure-activity relationships of a series of 5,9-dimethyl-2’-hydroxy-6,7-benzomorphan derivatives corroborating the criticality of the N-substituent nature. In that series of compounds the most promising was the 3-[(2R,6R,11R)-8-hydroxy-6,11-dimethyl-1,4,5,6-tetrahydro-2,6-methano-3-benzazocin-3(2H)-yl]-N-phenylpropanamide, named LP1, that was evaluated by in vitro and in vivo assays. The N-substituent nature conferred to LP1 affinity and intrinsic activity versus MOR and DOR, as detected by competition binding studies and functional in vitro assays. Moreover, in acute regimen, LP1, administered subcutaneously in male Sprague-Dawley rats, was as potent as morphine and its antinociceptive effect was completely naloxone-reversed [2]. Here, we evaluated whether the antinociceptive effect of LP1 was central or peripheral administering naloxone methiodide (NX-I) either intracerebroventricularly or subcutaneously. Moreover, using selective opioid antagonists for MOR, DOR and KOR naloxonazine (NLZ), naltrindole (NTI) and norBinaltorphimine (norBNI), respectively, we explored the opioid receptor subtypes involved in the antinociceptive effect of LP1. We also investigated LP1 effect on the antinociception DPDPE-induced to characterize its DOR profile better. In light of its MOR/DOR profile, we evaluated and compared the induction of tolerance to antinociceptive effects from treatment with LP1 and morphine. Data obtained by radiant tail flick test showed that LP1 acts prevalently in the central nervous system as a suitable MOR agonist able to counteract DPDPE analgesia. Moreover, unlike to morphine, LP1 showed a low capability to induce tolerance after chronic administration maintaining its antinociceptive effect until the ninth day [3]. Collected data described LP1 as a multitarget opioid ligand acting at the central level that is useful for the treatment of chronic pain.
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Utilizza questo identificativo per citare o creare un link a questo documento: http://hdl.handle.net/20.500.11769/103912
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