Long-lasting oral analgesic effects of N-protected aminophosphinic dual ENKephalinase inhibitors (DENKIs) in peripherally controlled pain
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- dc.contributor.author Bonnard, Elisabethca
- dc.contributor.author Poras, Hervéca
- dc.contributor.author Nadal i Roura, Xavier, 1980-ca
- dc.contributor.author Maldonado, Rafael, 1961-ca
- dc.contributor.author Fournié-Zaluski, Marie-Claudeca
- dc.contributor.author Roques, Bernard P.ca
- dc.date.accessioned 2015-03-23T08:49:21Z
- dc.date.available 2015-03-23T08:49:21Z
- dc.date.issued 2015ca
- dc.description.abstract The peripheral endogenous opioid system is critically involved in neuropathic and inflammatory pain generation as suggested by the modulation of opioid receptors expression and enkephalins (ENKs) release observed in these painful conditions. Accordingly, an innovative approach in the treatment of these nocifensive events is to increase and maintain high local concentrations of extracellular pain-evoked ENKs, by preventing their physiological enzymatic inactivation by two Zn metallopeptidases, the neutral endopeptidase (NEP, neprilysin, EC 3.4.24.11) and the neutral aminopeptidase (APN, EC 3.4.11.2). With this aim, new orally active dual ENKephalinase inhibitors (DENKIs) were designed as soluble prodrugs by introducing a N-terminal cleavable carbamate in the previously described aminophosphinic inhibitors. This induces long-lasting antinociceptive responses after oral administration, in various rodent models of inflammatory and neuropathic pain. These responses are mediated through stimulation of peripheral opioid receptors by DENKIs-protected ENKs as demonstrated by naloxone methiodide reversion. In all tested models, the most efficient prodrug 2a (PL265) was active, at least during 150-180 min, after single oral administration of 25-50 mg/kg in mice and of 100-200 mg/kg in rats. In models of neuropathic pain, both hyperalgesia and allodynia were markedly reduced. Interestingly, combination of inactive doses of 2a (PL265) and of the anti-epileptic drug gabapentin had synergistic effect on neuropathic pain. Pharmacokinetic studies of 2a (PL265) in rats show that the active drug is the only generated metabolite produced. These encouraging results have made 2a (PL265) a suitable candidate for clinical development.
- dc.format.mimetype application/pdfca
- dc.identifier.citation Bonnard E, Poras H, Nadal X, Maldonado R, Fournié-Zaluski MC, Roques BP. Long-lasting oral analgesic effects of N-protected aminophosphinic dual ENKephalinase inhibitors (DENKIs) in peripherally controlled pain. Pharmacol Res Perspect. 2015 Mar;3(2):e00116. DOI: 10.1002/prp2.116ca
- dc.identifier.doi http://dx.doi.org/10.1002/prp2.116
- dc.identifier.issn 2052-1707ca
- dc.identifier.uri http://hdl.handle.net/10230/23256
- dc.language.iso engca
- dc.publisher Wiley Open Accessca
- dc.relation.ispartof Pharmacology Research & Perspectives. 2015 Mar;3(2):e00116
- dc.rights © Elisabeth Bonard et al. Pharmacology Research & Perspectives published by John Wiley & Sons Ltd, British Pharmacological Society and American Society for Pharmacology and Experimental Therapeutics. This is an open access article under the terms of the Creative Commons Attribution-NonCommercial-NoDerivatives License, which permits use and distribution in any medium, provided the original work is properly cited, the use is non-commercial and no modifications or adaptations are madeca
- dc.rights.accessRights info:eu-repo/semantics/openAccessca
- dc.rights.uri http://creativecommons.org/licenses/by-nc-nd/3.0/
- dc.subject.other Analgèsics
- dc.subject.other Dolor
- dc.title Long-lasting oral analgesic effects of N-protected aminophosphinic dual ENKephalinase inhibitors (DENKIs) in peripherally controlled painca
- dc.type info:eu-repo/semantics/articleca
- dc.type.version info:eu-repo/semantics/publishedVersionca