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The Biological Consequences of Replacing d ‐Ala in Biphalin with Amphiphilic α‐Alkylserines
Author(s) -
Frączak Oliwia,
Lasota Anika,
Leśniak Anna,
Lipkowski Andrzej W.,
Olma Aleksandra
Publication year - 2014
Publication title -
chemical biology and drug design
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 0.59
H-Index - 77
eISSN - 1747-0285
pISSN - 1747-0277
DOI - 10.1111/cbdd.12305
Subject(s) - chemistry , peptide , stereochemistry , damgo , ligand (biochemistry) , selectivity , receptor , opioid peptide , residue (chemistry) , opioid receptor , amino acid , chirality (physics) , amphiphile , combinatorial chemistry , opioid , biochemistry , organic chemistry , chiral symmetry breaking , physics , quantum mechanics , nambu–jona lasinio model , quark , catalysis , polymer , copolymer
Biphalin, a synthetic opioid peptide with a broad affinity for all opioid receptors (δ, μ, and κ) and high antinociceptive activity, has been under extensive study as a potential analgesic drug. This study presents the synthesis and biological properties of four new analogues of biphalin containing amphiphilic α‐alkylserines in position 2 and 2′. The incorporation of bulky α,α‐disubstituted amino acids in the peptide chain using standard peptide chemistry is often unsuccessful. We synthesized depsipeptides, and then, the desired peptides were obtained by internal O , N ‐migration of the acyl residue from the hydroxyl to the amino group under mild basic conditions. The potency and selectivity of the new analogues were evaluated by a competitive receptor‐binding assay in the rat brain using [ 3 H]DAMGO (a μ ligand) and [ 3 H]DELT (a δ ligand). Their binding affinity is strongly dependent on the chirality of α‐alkylserine, as analogues containing ( R )‐α‐alkylserines displayed higher μ receptor affinity and selectivity than those incorporating the ( S )‐isomers.