Stereospecific synthesis of (2S)-2-methyl-3-(2',6'-dimethyl-4'-hydroxyphenyl)-propionic acid (Mdp) and its incorporation into an opioid peptide.
To examine the effect of replacing the N-terminal amino group in opioid peptides with a methyl group on biological activity, a stereospecific synthesis of the tyrosine analogue (2S)-2-methyl-3-(2',6'-dimethyl-4'-hydroxyphenyl)-propionic acid (Mdp) was performed. The enkephalin analogue (2S)-Mdp-D-Ala-Gly-Phe-Leu-NH2 turned out to be a quite potent delta opioid antagonist and a somewhat less potent mu antagonist, indicating that a positively charged N-terminal amino group is not a conditio sine qua non for the binding of opioid peptides to delta and mu receptors but may be required for signal transduction.
Lu
Y
Y
Laboratory of Chemical Biology and Peptide Research, Clinical Research Institute of Montreal, Quebec, Canada.
Weltrowska
G
G
Lemieux
C
C
Chung
N N
NN
Schiller
P W
PW
D000818:Animals; D001921:Brain; D004745:Enkephalins / Q000138:chemical synthesis / Q000494:pharmacology; D006168:Guinea Pigs; D007082:Ileum / Q000187:drug effects; D020128:Inhibitory Concentration 50; D008297:Male; D008566:Membranes / Q000737:chemistry; D051379:Mice; D009119:Muscle Contraction / Q000187:drug effects; D018847:Opioid Peptides / Q000138:chemical synthesis* / Q000378:metabolism / Q000494:pharmacology; D010636:Phenols; D011422:Propionates / Q000138:chemical synthesis / Q000494:pharmacology*; D011485:Protein Binding; D051381:Rats; D017465:Receptors, Opioid, delta / Q000037:antagonists & inhibitors* / Q000378:metabolism; D017450:Receptors, Opioid, mu / Q000037:antagonists & inhibitors / Q000378:metabolism; D013237:Stereoisomerism; D013329:Structure-Activity Relationship; D014649:Vas Deferens / Q000187:drug effects
C427005:2-methyl-3-(2',6'-dimethyl-4'-hydroxyphenyl)-propionic acid; D004745:Enkephalins; D018847:Opioid Peptides; D010636:Phenols; D011422:Propionates; D017465:Receptors, Opioid, delta; D017450:Receptors, Opioid, mu