Long-lasting oral analgesic effects of N-protected aminophosphinic dual ENKephalinase inhibitors (DENKIs) in peripherally controlled pain - CNRS - Centre national de la recherche scientifique Accéder directement au contenu
Article Dans Une Revue Pharmacology Research & Perspectives Année : 2015

Long-lasting oral analgesic effects of N-protected aminophosphinic dual ENKephalinase inhibitors (DENKIs) in peripherally controlled pain

Résumé

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.
Fichier principal
Vignette du fichier
hal-03292708.pdf (1.09 Mo) Télécharger le fichier
Origine : Fichiers éditeurs autorisés sur une archive ouverte

Dates et versions

hal-03292708 , version 1 (10-09-2021)

Identifiants

Citer

Elisabeth Bonnard, Herve Poras, Xavier Nadal, Rafael Maldonado, Marie-Claude Fournie-Zaluski, et al.. Long-lasting oral analgesic effects of N-protected aminophosphinic dual ENKephalinase inhibitors (DENKIs) in peripherally controlled pain. Pharmacology Research & Perspectives, 2015, 3 (2), ⟨10.1002/prp2.116⟩. ⟨hal-03292708⟩
28 Consultations
35 Téléchargements

Altmetric

Partager

Gmail Facebook X LinkedIn More