Probing opioid receptor interactions with azacycloalkane amino acids. Synthesis of a potent and selective ORL1 antagonist.
Azacycloalkane turn mimics 6-9 were used to explore the relationship between conformation and biological activity of peptide ligands to the opioid receptor-like (ORL1) receptor. Three azabicyclo[x.y.0]alkane amino acids and a 5-tBuPro type VI beta-turn mimic were introduced into peptides 10-13 by solid-phase synthesis on MBHA resin. Biological examination of peptides 10-13 showed two new antagonists (10 and 12) exhibiting increased selectivity for the ORL1 receptor.
Halab
Liliane
L
Département de Chimie, Université de Montréal, C. P. 6128, Succursale Centre Ville, Montréal, Québec, Canada H3C 3J7.
Becker
Jérôme A J
JA
Darula
Zsuzsanna
Z
Tourwé
Dirk
D
Kieffer
Brigitte L
BL
Simonin
Frédéric
F
Lubell
William D
WD
D000596:Amino Acids / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D000818:Animals; D001372:Aza Compounds / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D016466:CHO Cells; D019556:COS Cells; D006224:Cricetinae; D016244:Guanosine 5'-O-(3-Thiotriphosphate) / Q000378:metabolism; D008024:Ligands; D009292:Narcotic Antagonists; D010455:Peptides / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D017433:Protein Structure, Secondary; D011869:Radioligand Assay; D011957:Receptors, Opioid / Q000819:agonists; D013329:Structure-Activity Relationship; D000094942:Nociceptin Receptor
D000596:Amino Acids; D001372:Aza Compounds; D008024:Ligands; D009292:Narcotic Antagonists; D010455:Peptides; D011957:Receptors, Opioid; D016244:Guanosine 5'-O-(3-Thiotriphosphate); D000094942:Nociceptin Receptor