Synthesis and in vitro evaluation of a library of modified endomorphin 1 peptides.
Endomorphin 1 (Endo-1=Tyr-Pro-Trp-Phe-NH(2)), an endogenous opioid with high affinity and selectivity for mu-opioid receptors, mediates acute and neuropathic pain in rodents. To overcome metabolic instability and poor membrane permeability, the N- and C-termini of Endo-1 were modified by lipoamino acids (Laa) and/or sugars, and 2',6'-dimethyltyrosine (Dmt) replacement of Tyr. Analogues were assessed for mu-opioid receptor affinity, inhibition of cAMP accumulation, enzymatic stability, and permeability across Caco-2 cell monolayers. C-terminus modification decreased receptor affinity, while N-terminus C8-Laa improved stability and permeability with slight change in receptor affinity. Dmt provided a promising lead compound: [C8Laa-Dmt[1]]-Endo-1 is nine times more stable (t(1/2)=43.5min), >8-fold more permeable in Caco-2 cell monolayers, and exhibits 140-fold greater mu-opioid receptor affinity (K(imu)=0.08nM).
Koda
Yasuko
Y
School of Pharmacy, University of Queensland, St. Lucia, Brisbane, Qld 4072, Australia.
Del Borgo
Mark
M
Wessling
Susanne T
ST
Lazarus
Lawrence H
LH
Okada
Yoshio
Y
Toth
Istvan
I
Blanchfield
Joanne T
JT
D000818:Animals; D001682:Biological Availability; D018938:Caco-2 Cells; D002210:Caprylates / Q000138:chemical synthesis; D045744:Cell Line, Tumor; D002463:Cell Membrane Permeability; D006031:Glycosylation; D006801:Humans; D006900:Hydroxylation; D007850:Lauric Acids / Q000138:chemical synthesis; D050356:Lipid Metabolism; D009842:Oligopeptides / Q000138:chemical synthesis* / Q000378:metabolism*; D010446:Peptide Fragments / Q000378:metabolism; D019151:Peptide Library; D051381:Rats
D002210:Caprylates; D007850:Lauric Acids; D009842:Oligopeptides; D010446:Peptide Fragments; D019151:Peptide Library; C105293:endomorphin 1; C030358:lauric acid; C031492:octanoic acid