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.