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Pharmacological characterization of the nociceptin/orphanin FQ receptor non peptide antagonist Compound 24.
Eur J Pharmacol 2009; 614(1-3):50-7EJ

Abstract

Compound 24, 1-benzyl-N-[3-[spiroisobenzofuran-1(3H),4'-piperidin-1-yl]propyl] pyrrolidine-2-carboxamide was recently identified as a nociceptin/orphanin FQ (N/OFQ) peptide receptor (NOP) ligand. In this study, the in vitro and in vivo pharmacological profiles of Compound 24 were investigated. In vitro studies were performed measuring receptor and [(35)S]GTPgammaS binding and calcium mobilization in cells expressing the recombinant NOP receptor as well as using N/OFQ sensitive tissues. In vivo studies were conducted using the tail withdrawal assay in mice. Compound 24 produced a concentration-dependent displacement of [(3)H]N/OFQ binding to CHO(hNOP) cell membranes showing high affinity (pK(i) 9.62) and selectivity (1000 fold) over classical opioid receptors. Compound 24 antagonized with high potency the following in vitro effects of N/OFQ: stimulation of [(35)S]GTPgammaS binding in CHO(hNOP) cell membranes (pA(2) 9.98), calcium mobilization in CHO(hNOP) cells expressing the Galpha(qi5) chimeric protein (pK(B) 8.73), inhibition of electrically evoked twitches in the mouse (pA(2) 8.44) and rat (pK(B) 8.28) vas deferens, and in the guinea pig ileum (pK(B) 9.12). In electrically stimulated tissues, Compound 24 up to 1 microM did not modify the effects of classical opioid receptor agonists. Finally in vivo, in the mouse tail withdrawal assay, Compound 24 at 10 mg/kg antagonized the pronociceptive and antinociceptive effects of 1 nmol N/OFQ given supraspinally and spinally, respectively. Under the same experimental conditions Compound 24 did not affect the antinociceptive action of 3 nmol endomorphin-1 injected intrathecally. The present study demonstrated that Compound 24 is a pure, competitive, and highly potent non-peptide NOP receptor selective antagonist.

Authors+Show Affiliations

Department Experimental and Clinical Medicine, University of Ferrara, Ferrara, Italy.No affiliation info availableNo affiliation info availableNo affiliation info availableNo affiliation info availableNo affiliation info availableNo affiliation info availableNo affiliation info availableNo affiliation info availableNo affiliation info availableNo affiliation info available

Pub Type(s)

Journal Article
Research Support, Non-U.S. Gov't

Language

eng

PubMed ID

19445927

Citation

Fischetti, Carmela, et al. "Pharmacological Characterization of the Nociceptin/orphanin FQ Receptor Non Peptide Antagonist Compound 24." European Journal of Pharmacology, vol. 614, no. 1-3, 2009, pp. 50-7.
Fischetti C, Camarda V, Rizzi A, et al. Pharmacological characterization of the nociceptin/orphanin FQ receptor non peptide antagonist Compound 24. Eur J Pharmacol. 2009;614(1-3):50-7.
Fischetti, C., Camarda, V., Rizzi, A., Pelà, M., Trapella, C., Guerrini, R., ... Calo', G. (2009). Pharmacological characterization of the nociceptin/orphanin FQ receptor non peptide antagonist Compound 24. European Journal of Pharmacology, 614(1-3), pp. 50-7. doi:10.1016/j.ejphar.2009.04.054.
Fischetti C, et al. Pharmacological Characterization of the Nociceptin/orphanin FQ Receptor Non Peptide Antagonist Compound 24. Eur J Pharmacol. 2009 Jul 1;614(1-3):50-7. PubMed PMID: 19445927.
* Article titles in AMA citation format should be in sentence-case
TY - JOUR T1 - Pharmacological characterization of the nociceptin/orphanin FQ receptor non peptide antagonist Compound 24. AU - Fischetti,Carmela, AU - Camarda,Valeria, AU - Rizzi,Anna, AU - Pelà,Michela, AU - Trapella,Claudio, AU - Guerrini,Remo, AU - McDonald,John, AU - Lambert,David G, AU - Salvadori,Severo, AU - Regoli,Domenico, AU - Calo',Girolamo, Y1 - 2009/05/12/ PY - 2008/12/12/received PY - 2009/04/16/revised PY - 2009/04/29/accepted PY - 2009/5/19/entrez PY - 2009/5/19/pubmed PY - 2009/8/26/medline SP - 50 EP - 7 JF - European journal of pharmacology JO - Eur. J. Pharmacol. VL - 614 IS - 1-3 N2 - Compound 24, 1-benzyl-N-[3-[spiroisobenzofuran-1(3H),4'-piperidin-1-yl]propyl] pyrrolidine-2-carboxamide was recently identified as a nociceptin/orphanin FQ (N/OFQ) peptide receptor (NOP) ligand. In this study, the in vitro and in vivo pharmacological profiles of Compound 24 were investigated. In vitro studies were performed measuring receptor and [(35)S]GTPgammaS binding and calcium mobilization in cells expressing the recombinant NOP receptor as well as using N/OFQ sensitive tissues. In vivo studies were conducted using the tail withdrawal assay in mice. Compound 24 produced a concentration-dependent displacement of [(3)H]N/OFQ binding to CHO(hNOP) cell membranes showing high affinity (pK(i) 9.62) and selectivity (1000 fold) over classical opioid receptors. Compound 24 antagonized with high potency the following in vitro effects of N/OFQ: stimulation of [(35)S]GTPgammaS binding in CHO(hNOP) cell membranes (pA(2) 9.98), calcium mobilization in CHO(hNOP) cells expressing the Galpha(qi5) chimeric protein (pK(B) 8.73), inhibition of electrically evoked twitches in the mouse (pA(2) 8.44) and rat (pK(B) 8.28) vas deferens, and in the guinea pig ileum (pK(B) 9.12). In electrically stimulated tissues, Compound 24 up to 1 microM did not modify the effects of classical opioid receptor agonists. Finally in vivo, in the mouse tail withdrawal assay, Compound 24 at 10 mg/kg antagonized the pronociceptive and antinociceptive effects of 1 nmol N/OFQ given supraspinally and spinally, respectively. Under the same experimental conditions Compound 24 did not affect the antinociceptive action of 3 nmol endomorphin-1 injected intrathecally. The present study demonstrated that Compound 24 is a pure, competitive, and highly potent non-peptide NOP receptor selective antagonist. SN - 1879-0712 UR - https://www.unboundmedicine.com/medline/citation/19445927/Pharmacological_characterization_of_the_nociceptin/orphanin_FQ_receptor_non_peptide_antagonist_Compound_24_ L2 - https://linkinghub.elsevier.com/retrieve/pii/S0014-2999(09)00414-2 DB - PRIME DP - Unbound Medicine ER -