Synthesis and in vitro evaluation of a library of modified endomorphin 1 peptides

Yasuko Koda, Mark Pasqualino Del Borgo, Susanne T Wessling, Lawrence H Lazarus, Yoshio Okada, Istvan Toth, Joanne T Blanchfield

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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).
Original languageEnglish
Pages (from-to)6286 - 6296
Number of pages11
JournalBioorganic & Medicinal Chemistry
Issue number11
Publication statusPublished - 2008

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