Role of 2',6'-dimethyl-l-tyrosine (Dmt) in some opioid lead compounds.
Here we evaluated how the interchange of the amino acids 2',6'-dimethyl-L-tyrosine (Dmt), 2',6'-difluoro-L-tyrosine (Dft), and tyrosine in position 1 can affect the pharmacological characterization of some reference opioid peptides and pseudopeptides. Generally, Dft and Tyr provide analogues with a similar pharmacological profile, despite different pK(a) values. Dmt/Tyr(Dft) replacement gives activity changes depending on the reference opioid in which the modification was made. Whereas, H-Dmt-Tic-Asp *-Bid is a potent and selective delta agonist (MVD, IC(50)=0.12nM); H-Dft-Tic-Asp *-Bid and H-Tyr-Tic-Asp *-Bid are potent and selective delta antagonists (pA(2)=8.95 and 8.85, respectively). When these amino acids are employed in the synthesis of deltorphin B and its Dmt(1) and Dft(1) analogues, the three compounds maintain a very similar delta agonism (MVD, IC(50) 0.32-0.53 nM) with a decrease in selectivity relative to the Dmt(1) analogue. In the less selective H-Dmt-Tic-Gly *-Bid the replacement of Dmt with Dft and Tyr retains the delta agonism but with a decrease in potency. Antagonists containing the Dmt-Tic pharmacophore do not support the exchange of Dmt with Dft or Tyr.
Balboni
Gianfranco
G
Department of Toxicology, University of Cagliari, I-09124 Cagliari, Italy.
Marzola
Erika
E
Sasaki
Yusuke
Y
Ambo
Akihiro
A
Marczak
Ewa D
ED
Lazarus
Lawrence H
LH
Salvadori
Severo
S
D000701:Analgesics, Opioid / Q000737:chemistry* / Q000494:pharmacology*; D000818:Animals; D006168:Guinea Pigs; D008297:Male; D009292:Narcotic Antagonists; D018847:Opioid Peptides / Q000737:chemistry* / Q000494:pharmacology*; D051381:Rats; D017207:Rats, Sprague-Dawley; D011957:Receptors, Opioid / Q000819:agonists / Q000378:metabolism*; D017465:Receptors, Opioid, delta / Q000819:agonists / Q000037:antagonists & inhibitors / Q000378:metabolism; D014443:Tyrosine / Q000031:analogs & derivatives* / Q000737:chemistry / Q000494:pharmacology
D000701:Analgesics, Opioid; D009292:Narcotic Antagonists; D018847:Opioid Peptides; D011957:Receptors, Opioid; D017465:Receptors, Opioid, delta; C076121:2',6'-dimethyltyrosine; C025200:3,5-difluorotyrosine; D014443:Tyrosine