The simultaneous targeting of opioid receptors could produce an improved antinociception with fewer incidence of undesirable effects, such as tolerance. Thus, multitarget opioid ligands are potential drugs for chronic pain management. Particularly, 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 reported that the benzomorphan-based compound LP1 (3-[(2R,6R,11R)-8-hydroxy-6,11-dimethyl-1,4,5,6-tetrahydro-2,6-methano-3-benzazocin-3(2H)-yl]-N-phenylpropanamide), is a MOR-DOR ligand 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). In this study, we evaluated whether the antinociceptive effect of LP1 was central or peripheral administering naloxone methiodide (NX-I) either intracerebroventricularly or subcutaneously. To assess which opioid receptor subtypes are involved in LP1 antinociceptive effect, we used the selective MOR, DOR and KOR antagonists, naloxonazine (NLZ), naltrindole (NTI) and nor-binaltorphimine (norBNI), respectively. 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/DOR antagonist and, unlike to morphine, showed a low capability to induce tolerance after chronic administration (3). Collected data described LP1 as a multitarget opioid ligand useful for the treatment of chronic pain (4). References (1) Dietis, N.; Guerrini, R.; Calò, G. et al. Br. J. Anaesth. 2009, 103, 38-49. (2) Pasquinucci, L.; Prezzavento, O.; Marrazzo, A. et al. Bioorg. Med. Chem. 2010, 18, 4975-82. (3) Pasquinucci, L.; Parenti, C.; Turnaturi R. et al2012, 90, 66-70. (4) Parenti, C.; Turnaturi, R.; Aricò, G. et al. . Life Sci. in press.

The benzomorphan-based compound LP1 is a central acting MOR agonist/DOR antagonist suitable for chronic pain treatment

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

Abstract

The simultaneous targeting of opioid receptors could produce an improved antinociception with fewer incidence of undesirable effects, such as tolerance. Thus, multitarget opioid ligands are potential drugs for chronic pain management. Particularly, 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 reported that the benzomorphan-based compound LP1 (3-[(2R,6R,11R)-8-hydroxy-6,11-dimethyl-1,4,5,6-tetrahydro-2,6-methano-3-benzazocin-3(2H)-yl]-N-phenylpropanamide), is a MOR-DOR ligand 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). In this study, we evaluated whether the antinociceptive effect of LP1 was central or peripheral administering naloxone methiodide (NX-I) either intracerebroventricularly or subcutaneously. To assess which opioid receptor subtypes are involved in LP1 antinociceptive effect, we used the selective MOR, DOR and KOR antagonists, naloxonazine (NLZ), naltrindole (NTI) and nor-binaltorphimine (norBNI), respectively. 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/DOR antagonist and, unlike to morphine, showed a low capability to induce tolerance after chronic administration (3). Collected data described LP1 as a multitarget opioid ligand useful for the treatment of chronic pain (4). References (1) Dietis, N.; Guerrini, R.; Calò, G. et al. Br. J. Anaesth. 2009, 103, 38-49. (2) Pasquinucci, L.; Prezzavento, O.; Marrazzo, A. et al. Bioorg. Med. Chem. 2010, 18, 4975-82. (3) Pasquinucci, L.; Parenti, C.; Turnaturi R. et al2012, 90, 66-70. (4) Parenti, C.; Turnaturi, R.; Aricò, G. et al. . Life Sci. in press.
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Utilizza questo identificativo per citare o creare un link a questo documento: http://hdl.handle.net/20.500.11769/109222
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