title: The biological consequences of replacing D-Ala in biphalin with amphiphilic α-alkylserines.
abstract: 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.
authors.affiliation: Institute of Organic Chemistry, Lodz University of Technology, Żeromskiego 116, 90-924, Łódź, Poland.
authors.forename: Oliwia
authors.initials: O
authors.lastname: Frączak
authors.forename: Anika
authors.initials: A
authors.lastname: Lasota
authors.forename: Anna
authors.initials: A
authors.lastname: Leśniak
authors.forename: Andrzej W
authors.initials: AW
authors.lastname: Lipkowski
authors.forename: Aleksandra
authors.initials: A
authors.lastname: Olma
mesh_terms: D000700:Analgesics / Q000737:chemistry* / Q000494:pharmacology*; D000818:Animals; D001921:Brain / Q000378:metabolism; D004745:Enkephalins / Q000737:chemistry* / Q000494:pharmacology*; D008958:Models, Molecular; D051381:Rats; D011957:Receptors, Opioid / Q000378:metabolism*; D012694:Serine / Q000737:chemistry / Q000494:pharmacology
chemical_list: D000700:Analgesics; D004745:Enkephalins; D011957:Receptors, Opioid; D012694:Serine; C053673:biphalin
keywords: O,N-migration; O-acyl isopeptides; amphiphilic amino acids; biphalin analogues; opioid activities; opioid peptides; α-alkylserines