Potent Opioid Peptide Agonists Containing 4′‐[N‐((4′‐phenyl)‐phenethyl)carboxamido]phenylalanine (Bcp) in Place of Tyr |
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Authors: | Grazyna Weltrowska Thi M‐D Nguyen Carole Lemieux Nga N Chung Peter W Schiller |
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Institution: | Laboratory of Chemical Biology and Peptide Research, Clinical Research Institute of Montreal, 110 Pine Avenue West, Montreal, Que., Canada H2W 1R7 |
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Abstract: | Analogues of the opioid peptides H‐Tyr‐cd ‐Cys‐Gly‐Phe(pNO2)‐d ‐Cys]NH2 (non‐selective), H‐Tyr‐d ‐Arg‐Phe‐Lys‐NH2 (μ‐selective) and dynorphin A(1‐11)‐NH2 (κ‐selective) containing 4′‐N‐((4′‐phenyl)‐phenethyl)carboxamido]phenylanine (Bcp) in place of Tyr1 were synthesized. All three Bcp1‐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 Tyr1‐containing parent peptides. The cyclic peptide H‐Bcp‐cd ‐Cys‐Gly‐Phe(pNO2)‐d ‐Cys]NH2 turned out to be an extraordinarily potent, μ‐selective opioid agonist, whereas the Bcp1‐analogue of dynorphin A(1‐11)‐NH2 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. |
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Keywords: | 4′ ‐[N‐((4′ ‐phenyl)‐phenethyl)carboxamido]phenylalanine opioid activity profiles opioid peptide analogues opioid peptide SAR peptide synthesis |
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