The nociceptin pharmacophore site for opioid receptor binding derived from the NMR structure and bioactivity relationships.
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.
Orsini
Michael J
MJ
Johnson & Johnson Pharmaceutical Research and Development, LLC, Raritan, New Jersey 08869, USA.
Nesmelova
Irina
I
Young
Helen C
HC
Hargittai
Balazs
B
Beavers
Mary Pat
MP
Liu
Jingchun
J
Connolly
Peter J
PJ
Middleton
Steven A
SA
Mayo
Kevin H
KH
D000409:Alanine / Q000737:chemistry; D000595:Amino Acid Sequence; D001665:Binding Sites; D001667:Binding, Competitive; D002118:Calcium / Q000737:chemistry; D002460:Cell Line; D002462:Cell Membrane / Q000378:metabolism; D019992:Databases as Topic; D004305:Dose-Response Relationship, Drug; D015195:Drug Design; D006801:Humans; D007700:Kinetics; D009682:Magnetic Resonance Spectroscopy / Q000379:methods*; D008823:Micelles; D008958:Models, Molecular; D008969:Molecular Sequence Data; D009690:Nucleic Acid Conformation; D018847:Opioid Peptides / Q000737:chemistry* / Q000378:metabolism; D010455:Peptides / Q000737:chemistry; D011485:Protein Binding; D011487:Protein Conformation; D017434:Protein Structure, Tertiary; D011957:Receptors, Opioid / Q000737:chemistry*; D012967:Sodium Dodecyl Sulfate / Q000737:chemistry; D013329:Structure-Activity Relationship; D000094942:Nociceptin Receptor; D000097629:Nociceptin
D000409:Alanine; D002118:Calcium; D008823:Micelles; D018847:Opioid Peptides; D010455:Peptides; D011957:Receptors, Opioid; D012967:Sodium Dodecyl Sulfate; D000094942:Nociceptin Receptor; D000097629:Nociceptin; C000722283:OPRL1 protein, human