Biphalin analogs containing β3-homo-amino acids at the 4,4′ positions: Synthesis and opioid activity profiles

In this paper we present the synthesis and biological properties of new biphalin α,β-hybrides, modified in position 4,4′ with β3-homo-amino acids containing hydrazine and 1,2-phenylenediamine linkers. Competitive receptor binding assay shows that analog (Tyr-d-Ala-Gly-β3-h-p-NO2PheNH)2 and (Tyr-d-Ala-Gly-β3-h-p-NO2Phe)2-1,2-phenylenediamine are the most active peptides and slightly μ or δ selective respectively. Structural analysis of analogs with hydrazine and 1,2-phenylenediamine bridges shows high similarity with topographical locations and distances between functional groups of both hybridized pharmacophores. (Tyr-d-Ala-Gly-β3-h-p-NO2PheNH)2 produced greater antinociceptive effect compared to biphalin and morphine after i.t. administration.