Receptor selectivity of enkephalin analogs carrying artificial address peptides.
The synthetic [Leu]enkephalin analogs YGGFLGP(KS'S'S')2-OMe (S' represents Sar residue, ENK-S'8), YGGFLGP(KPPP)2-OMe (ENK-P8), and YGGFLGP(KA'LA')2-OMe (A' represents 2-aminoisobutyric acid (Aib), ENK-A'8) were designed to investigate the role of membrane affinity in opioid receptor binding. CD measurement in ethanol revealed that ENK-S'8 took a random coil conformation, while ENK-P8 and ENK-A'8 partly adopted a 3(1)- and alpha-helical conformation, respectively. ENK-A'8 was shown to be distributed to lipid bilayer membrane due to the amphiphilic alpha-helical structure, while ENK-S'8 and ENK-P8 stayed in aqueous phase. Opioid receptor affinities ENK-S'8 and ENK-P8 were similar to [Leu]enkephalinamide, indicating that the connection of hydrophilic peptide segments to the C-terminal of [Leu]enkephalinamide did not affect the receptor affinity. On the other hand, delta- and mu-receptor affinities of ENK-A'8 were about 1/20 and 1/6 times, respectively, those of [Leu]enkephalinamide. Therefore, ENK-A'8 has higher selectivity for mu-receptor than [Leu]enkephalinamide. These results are explained in terms of the membrane compartment concept proposed by Schwyzer.
Kimura
S
S
Department of Polymer Chemistry, Kyoto University, Japan.
Sasaki-Yagi
Y
Y
Imanishi
Y
Y
D000595:Amino Acid Sequence; D000818:Animals; D001692:Biological Transport; D002417:Cattle; D004743:Enkephalin, Leucine / Q000031:analogs & derivatives* / Q000378:metabolism; D008567:Membranes, Artificial; D008969:Molecular Sequence Data; D011487:Protein Conformation; D011957:Receptors, Opioid / Q000378:metabolism*; D013329:Structure-Activity Relationship
D008567:Membranes, Artificial; D011957:Receptors, Opioid; C065589:enkephalin-Leu, Gly-Pro-(Lys-Aib-Leu-Aib)(2)-OMe-; C065588:enkephalin-Leu, Gly-Pro-(Lys-Pro-Pro-Pro)2-OMe-; C065587:enkephalin-Leu, Gly-Pro-(Lys-Sar-Sar-Sar)(2)-OMe-; D004743:Enkephalin, Leucine