Synthesis of stereoisomeric analogues of endomorphin-2, H-Tyr-Pro-Phe-Phe-NH(2), and examination of their opioid receptor binding activities and solution conformation.
All sixteen stereoisomeric analogues of endomorphin-2 (H-Tyr-Pro-Phe-Phe-NH(2)) were synthesized by Fmoc-strategy using solid phase methods. Although synthetic endomorphin-2 exhibited similar mu- and delta-opioid receptor-binding activity to the natural compound, endomorphin-2 analogues containing d-amino acid isomers exhibited lower interaction with mu-receptors depending on the particular combination. The data clearly indicated that the three dimensional structure of endomorphin-2 with the natural l-configuration was the most suitable for binding within the mu receptor, but specific residues are important for activity. Circular dichroism studies verified that changes in chirality of amino acids in the endomorphin-2 sequence resulted in structural conformation. These alterations significantly reduced the specificity for mu-receptor-binding sites.
Okada
Y
Y
Faculty of Pharmaceutical Sciences, Kobe Gakuin University, Nishi-ku, Kobe, 651-2180, Japan. okada@pharm.kobegakuin.ac.jp
Fukumizu
A
A
Takahashi
M
M
Shimizu
Y
Y
Tsuda
Y
Y
Yokoi
T
T
Bryant
S D
SD
Lazarus
L H
LH
D000818:Animals; D009842:Oligopeptides / Q000138:chemical synthesis / Q000737:chemistry* / Q000378:metabolism; D011485:Protein Binding; D011487:Protein Conformation; D011869:Radioligand Assay; D051381:Rats; D017207:Rats, Sprague-Dawley; D011957:Receptors, Opioid / Q000737:chemistry* / Q000378:metabolism; D013237:Stereoisomerism
D009842:Oligopeptides; D011957:Receptors, Opioid; C105294:endomorphin 2