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Potent Opioid Peptide Agonists Containing 4′‐[ N ‐((4′‐phenyl)‐phenethyl)carboxamido]phenylalanine (Bcp) in Place of Tyr
Author(s) -
Weltrowska Grazyna,
Nguyen Thi M.D.,
Lemieux Carole,
Chung Nga N.,
Schiller* Peter W.
Publication year - 2008
Publication title -
chemical biology and drug design
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 0.59
H-Index - 77
eISSN - 1747-0285
pISSN - 1747-0277
DOI - 10.1111/j.1747-0285.2008.00720.x
Subject(s) - chemistry , dynorphin , stereochemistry , dynorphin a , agonist , nociceptin receptor , opioid peptide , peptide , opioid receptor , receptor , phenylalanine , substituent , partial agonist , opioid , biochemistry , amino acid
Analogues of the opioid peptides H‐Tyr‐c[ d ‐Cys‐Gly‐Phe( p NO 2 )‐ d ‐Cys]NH 2 (non‐selective), H‐Tyr‐ d ‐Arg‐Phe‐Lys‐NH 2 (μ‐selective) and dynorphin A(1‐11)‐NH 2 (κ‐selective) containing 4′‐[ N ‐((4′‐phenyl)‐phenethyl)carboxamido]phenylanine (Bcp) in place of Tyr 1 were synthesized. All three Bcp 1 ‐opioid peptides retained high μ opioid receptor binding affinity, but showed very significant differences in the opioid receptor selectivity profiles as compared with the corresponding Tyr 1 ‐containing parent peptides. The cyclic peptide H‐Bcp‐c[ d ‐Cys‐Gly‐Phe( p NO 2 )‐ d ‐Cys]NH 2 turned out to be an extraordinarily potent, μ‐selective opioid agonist, whereas the Bcp 1 ‐analogue of dynorphin A(1‐11)‐NH 2 displayed partial agonism at the μ receptor. The obtained results suggest that the large biphenylethyl substituent contained in these compounds may engage in a hydrophobic interaction with a receptor subsite and thereby may play a role in the ligand’s ability to induce a specific receptor conformation or to bind to a distinct receptor conformation in a situation of conformational receptor heterogeneity.