Endomorphin 2 analogues containing Dmp residue as an aromatic amino acid surrogate with high mu-opioid receptor affinity and selectivity.
To investigate the effectiveness of a 2',6'-dimethylphenylalanine (Dmp) residue as an aromatic amino acid surrogate, endomorphin 2 (EM(2): Tyr-Pro-Phe-Phe-NH(2)) analogues were prepared, in which the constitutive aromatic amino acids (Tyr(1), Phe(3), or Phe(4)) were replaced by Dmp or its isomer, D-Dmp. Replacement of Phe(3) by Dmp increased the affinity over 10-fold for both mu- and delta-opioid receptors, without affecting receptor selectivity. In contrast, replacement of Phe(4) considerably reduced the mu-receptor affinity and selectivity. These data indicated that the Dmp-substitution of Phe(3), but not Phe(4), in EM(2) is favorable for improving mu-receptor specificity. Inversion of the chirality of the substituted Dmp residue resulted in marked decrease in the mu-receptor affinity. Replacement of Tyr(1) by Dmp yielded an analogue that exhibited only a limited decrease in mu-receptor affinity and GPI potency, despite the lack of a phenolic hydroxyl group at the N-terminal residue. In contrast, D-Dmp(1)- or Phe(1)-substitution of Tyr(1) resulted in a significant decrease in mu-receptor affinity and GPI potency. These results suggested that the Dmp residue can mimic Tyr(1), which is one of the critical structural elements of opioid peptides.
Sasaki
Yusuke
Y
Tohoku Pharmaceutical University, 4-1 Komatsushima 4-chome, Aoba-ku, Sendai 981-8558, Japan. yasaki@tohoku-pharm.ac.jp
Sasaki
Ai
A
Niizuma
Hideko
H
Goto
Harumi
H
Ambo
Akihiro
A
D024322:Amino Acids, Aromatic / Q000494:pharmacology*; D000701:Analgesics, Opioid / Q000138:chemical synthesis* / Q000494:pharmacology*; D000818:Animals; D055598:Chemical Phenomena; D002627:Chemistry, Physical; D006168:Guinea Pigs; D066298:In Vitro Techniques; D008297:Male; D051379:Mice; D009119:Muscle Contraction / Q000187:drug effects; D009842:Oligopeptides / Q000138:chemical synthesis* / Q000494:pharmacology*; D017465:Receptors, Opioid, delta / Q000187:drug effects; D017450:Receptors, Opioid, mu / Q000187:drug effects*; D014649:Vas Deferens / Q000187:drug effects
D024322:Amino Acids, Aromatic; D000701:Analgesics, Opioid; D009842:Oligopeptides; D017465:Receptors, Opioid, delta; D017450:Receptors, Opioid, mu; C105294:endomorphin 2