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Peptides. 2010 Jun;31(6):1194-204. doi: 10.1016/j.peptides.2010.03.015. Epub 2010 Mar 20.

Pharmacological profile and antiparkinsonian properties of the novel nociceptin/orphanin FQ receptor antagonist 1-[1-cyclooctylmethyl-5-(1-hydroxy-1-methyl-ethyl)-1,2,3,6-tetrahydro-pyridin-4-yl]-3-ethyl-1,3-dihydro-benzoimidazol-2-one (GF-4).

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Department of Experimental and Clinical Medicine, Section of Pharmacology, University of Ferrara, Ferrara Italy.


In this study we provided a pharmacological characterization of the recently synthesized nociceptin/orphanin FQ (N/OFQ) peptide receptor (NOP) antagonist 1-[1-Cyclooctylmethyl-5-(1-hydroxy-1-methyl-ethyl)-1,2,3,6-tetrahydro-pyridin-4-yl]-3-ethyl-1,3-dihydro-benzoimidazol-2-one (GF-4) and investigated its antiparkinsonian properties. GF-4 inhibited N/OFQ binding to CHO(hNOP) cell membranes (pK(i) 7.46), and antagonized N/OFQ effects in a calcium mobilization assay and electrically stimulated isolated tissues (pK(B) 7.27-7.82), showing a approximately 5-fold selectivity over classical opioid receptors. In vivo, GF-4 dually modulated stepping activity in wild-type mice, causing facilitation in the 0.01-10mg/kg dose range and inhibition at 30mg/kg. These effects were mediated by NOP receptors since GF-4 was ineffective in NOP receptor knock-out mice. Antiparkinsonian properties of GF-4 were investigated in 6-hydroxydopamine hemilesioned rats. GF-4 ameliorated akinesia, bradykinesia and overall gait ability in the 0.1-10mg/kg dose range, but inhibited motor activity at 30mg/kg. To investigate the circuitry underlying motor facilitating and inhibitory effects of GF-4, microdialysis coupled to behavioral testing (akinesia test) was performed. An anti-akinetic dose of GF-4 (1mg/kg) reduced glutamate (GLU) and enhanced GABA release in SNr, while the pro-akinetic dose of GF-4 (30mg/kg) evoked opposite effects. Moreover, the anti-akinetic dose of GF-4 reduced GABA and increased GLU release in ventro-medial thalamus, the pro-akinetic dose decreasing GABA without affecting GLU release in this area. We conclude that GF-4 is an effective NOP receptor antagonist able to attenuate parkinsonian-like symptoms in vivo via inhibition of the nigro-thalamic pathway.

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