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  • Anti-Parkinsonian and anti-dyskinetic profiles of two novel potent and selective nociceptin/orphanin FQ receptor agonists.

Anti-Parkinsonian and anti-dyskinetic profiles of two novel potent and selective nociceptin/orphanin FQ receptor agonists.

British journal of pharmacology (2017-12-13)
Ludovico Arcuri, Salvatore Novello, Martina Frassineti, Daniela Mercatelli, Clarissa Anna Pisanò, Ilaria Morella, Stefania Fasano, Blair V Journigan, Michael E Meyer, Willma E Polgar, Riccardo Brambilla, Nurulain T Zaveri, Michele Morari
ABSTRACT

We previously showed that nociceptin/orphanin FQ opioid peptide (NOP) receptor agonists attenuate the expression of levodopa-induced dyskinesia in animal models of Parkinson's disease. We now investigate the efficacy of two novel, potent and chemically distinct NOP receptor agonists, AT-390 and AT-403, to improve Parkinsonian disabilities and attenuate dyskinesia development and expression. Binding affinity and functional efficacy of AT-390 and AT-403 at the opioid receptors were determined in radioligand displacement assays and in GTPγS binding assays respectively, conducted in CHO cells. Their anti-Parkinsonian activity was evaluated in 6-hydroxydopamine hemi-lesioned rats whereas the anti-dyskinetic properties were assessed in 6-hydroxydopamine hemi-lesioned rats chronically treated with levodopa. The ability of AT-403 to inhibit the D1 receptor-induced phosphorylation of striatal ERK was investigated. AT-390 and AT-403 selectively improved akinesia at low doses and disrupted global motor activity at higher doses. AT-403 palliated dyskinesia expression without causing sedation in a narrow therapeutic window, whereas AT-390 delayed the appearance of abnormal involuntary movements and increased their duration at doses causing sedation. AT-403 did not prevent the priming to levodopa, although it significantly inhibited dyskinesia on the first day of administration. AT-403 reduced the ERK phosphorylation induced by SKF38393 in vitro and by levodopa in vivo. NOP receptor stimulation can provide significant albeit mild anti-dyskinetic effect at doses not causing sedation. The therapeutic window, however, varies across compounds. AT-403 could be a potent and selective tool to investigate the role of NOP receptors in vivo.

MATERIALS
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Brand
Product Description

Sigma-Aldrich
Goat Anti-Rabbit IgG Antibody, HRP-conjugate, 1 mg/mL, Upstate®
Sigma-Aldrich
Anti-phospho-Erk1/2 (Thr202/Tyr204, Thr185/Tyr187)Antibody, recombinant clone AW39R, rabbit monoclonal, clone AW39R, Upstate®, from rabbit