New analogs of the endogenous opioid agonist endomorphin-2 (EM-2, H-Tyr-Pro-Phe-Phe-NH2) have been obtained by introducing modified tyrosines at the position 1 of the sequence. For all analogs, the cis/trans conformation ratio about the tyramine-Pro amide bond, lipophilicity, receptor affinities, and functional activities, have been determined. Among the novel derivatives, [Dmt(3′-Cl)]1EM-2 (4) stood out for its subnanomolar μ-opioid receptor affinity and potent agonist activity, superior to that of the parent peptide EM-2. Hybrid quantum mechanics/molecular mechanics docking computations supported the cis tyramine-Pro bioactive conformation, and allowed us to analyze the contribution of the substituents of the “message” tyramine to binding, highlighting the role of halogen-bonding in the higher receptor affinity of peptide 4.
Wtorek K., Artali R., Piekielna-Ciesielska J., Koszuk J., Kluczyk A., Gentilucci L., et al. (2019). Endomorphin-2 analogs containing modified tyrosines: Biological and theoretical investigation of the influence on conformation and pharmacological profile. EUROPEAN JOURNAL OF MEDICINAL CHEMISTRY, 179, 527-536 [10.1016/j.ejmech.2019.06.077].
Endomorphin-2 analogs containing modified tyrosines: Biological and theoretical investigation of the influence on conformation and pharmacological profile
Artali R.;Gentilucci L.
Supervision
;
2019
Abstract
New analogs of the endogenous opioid agonist endomorphin-2 (EM-2, H-Tyr-Pro-Phe-Phe-NH2) have been obtained by introducing modified tyrosines at the position 1 of the sequence. For all analogs, the cis/trans conformation ratio about the tyramine-Pro amide bond, lipophilicity, receptor affinities, and functional activities, have been determined. Among the novel derivatives, [Dmt(3′-Cl)]1EM-2 (4) stood out for its subnanomolar μ-opioid receptor affinity and potent agonist activity, superior to that of the parent peptide EM-2. Hybrid quantum mechanics/molecular mechanics docking computations supported the cis tyramine-Pro bioactive conformation, and allowed us to analyze the contribution of the substituents of the “message” tyramine to binding, highlighting the role of halogen-bonding in the higher receptor affinity of peptide 4.I documenti in IRIS sono protetti da copyright e tutti i diritti sono riservati, salvo diversa indicazione.
