TY - JOUR
T1 - Structural and biological exploration of Phe3-Phe 4-modified endomorphin-2 peptidomimetics
AU - Lesma, Giordano
AU - Salvadori, Severo
AU - Airaghi, Francesco
AU - Murray, Thomas F.
AU - Recca, Teresa
AU - Sacchetti, Alessandro
AU - Balboni, Gianfranco
AU - Silvani, Alessandra
PY - 2013/8/8
Y1 - 2013/8/8
N2 - This study reports on our ongoing investigation on hybrid EM-2 analogues, in which the great potential of β-amino acids was exploited to generate multiple conformational modifications at the key positions 3 and 4 of the parent peptide. The effect on the opioid binding affinity was evaluated, by means of ligand stimulated binding assays, which indicated a high nanomolar affinity toward the μ-receptor, with appreciable μ/δ selectivity, for some of the new compounds. The three-dimensional properties of the high affinity μ opioid receptor (MOR) ligands were investigated by proton nuclear magnetic resonance, molecular dynamics, and docking studies. In solution, the structures showed extended conformations, which are in agreement with the commonly accepted pharmacophore model for EM-2. From docking studies on an active form of the MOR model, different ligand-receptor interactions have been identified, thus confirming the ability of active compounds to assume a biologically active conformation.
AB - This study reports on our ongoing investigation on hybrid EM-2 analogues, in which the great potential of β-amino acids was exploited to generate multiple conformational modifications at the key positions 3 and 4 of the parent peptide. The effect on the opioid binding affinity was evaluated, by means of ligand stimulated binding assays, which indicated a high nanomolar affinity toward the μ-receptor, with appreciable μ/δ selectivity, for some of the new compounds. The three-dimensional properties of the high affinity μ opioid receptor (MOR) ligands were investigated by proton nuclear magnetic resonance, molecular dynamics, and docking studies. In solution, the structures showed extended conformations, which are in agreement with the commonly accepted pharmacophore model for EM-2. From docking studies on an active form of the MOR model, different ligand-receptor interactions have been identified, thus confirming the ability of active compounds to assume a biologically active conformation.
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U2 - 10.1021/ml400189r
DO - 10.1021/ml400189r
M3 - Article
AN - SCOPUS:84881435753
VL - 4
SP - 795
EP - 799
JO - ACS Medicinal Chemistry Letters
JF - ACS Medicinal Chemistry Letters
SN - 1948-5875
IS - 8
ER -