A selective small molecule NOP (ORL-1 receptor) partial agonist for the treatment of anxiety

[Display omitted] Small molecule (1) has been identified as a selective partial agonist of Opioid Receptor Like-1 (ORL-1) with potential utility for the treatment of anxiety and other disorders. Nociceptin (orphanin FQ) is an endogenous peptide ligand that binds to ORL-1, however it does not bind th...

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Veröffentlicht in:	Bioorganic & medicinal chemistry letters 2015-02, Vol.25 (3), p.602-606
Hauptverfasser:	Ross, Tina Morgan, Battista, Kathleen, Bignan, Gilles C., Brenneman, Doug E., Connolly, Peter J., Liu, Jingchun, Middleton, Steven A., Orsini, Michael, Reitz, Allen B., Rosenthal, Dan I., Scott, Malcolm K., Vaidya, Anil H.
Format:	Artikel
Sprache:	eng
Schlagworte:	Animals Anxiety - drug therapy Disease Models, Animal Drug discovery Motor Activity - drug effects Nociceptin Nociceptin Receptor NOP receptor Opioid Peptides - chemistry Opioid Peptides - metabolism Opioid receptor-like receptor-1 Orphanin FQ Protein Binding Rats Receptors, Opioid - agonists Receptors, Opioid - metabolism Small Molecule Libraries - chemistry Small Molecule Libraries - pharmacology Small Molecule Libraries - therapeutic use Spiro Compounds - chemistry Spiro Compounds - pharmacology Spiro Compounds - therapeutic use Structure-Activity Relationship
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Zusammenfassung:	[Display omitted] Small molecule (1) has been identified as a selective partial agonist of Opioid Receptor Like-1 (ORL-1) with potential utility for the treatment of anxiety and other disorders. Nociceptin (orphanin FQ) is an endogenous peptide ligand that binds to ORL-1, however it does not bind the classical δ, μ and κ opioid receptors with high affinity. The synthesis of 1 involved using a molecular diversity approach, to rapidly advance a library of compounds for biological testing. A lead selective potent partial agonist (35-fold ORL-1/Mu) progressed to ORL-1 (NOP or OP4) proof of concept testing in advanced studies. The synthetic approach and biological data for the related chemical series will be presented.
ISSN:	0960-894X 1464-3405
DOI:	10.1016/j.bmcl.2014.12.015