The nociceptin pharmacophore site for opioid receptor binding derived from the NMR structure and bioactivity relationships

Michael J. Orsini, Irina Nesmelova, Helen C. Young, Balazs Hargittai, Mary Pat Beavers, Jingchun Liu, Peter J. Connolly, Steven A. Middleton, Kevin H. Mayo

Research output: Contribution to journalArticlepeer-review

24 Scopus citations

Abstract

Nociceptin, a 17 amino acid opioid-like peptide that has an inhibitory effect on synaptic transmission in the nervous system, is involved in learning, memory, attention, and emotion and is also implicated in the perception of pain and visual, auditory, and olfactory functions. In this study, we investigated the NMR solution structure of nociceptin in membrane-like environments (trifluoroethanol and SDS micelles) and found it to have a relatively stable helix conformation from residues 4-17 with functionally important N-terminal residues being folded aperidoically on top of the helix. In functional assays for receptor binding and calcium flux, alanine-scanning variants of nociceptin indicated that functionally important residues generally followed helix periodicity, consistent with the NMR structural model. Structure-activity relationships allowed identification of pharmacophore sites that were used in small molecule data base searches, affording hits with demonstrated nociceptin receptor binding affinities.

Original languageEnglish (US)
Pages (from-to)8134-8142
Number of pages9
JournalJournal of Biological Chemistry
Volume280
Issue number9
DOIs
StatePublished - Mar 4 2005

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