New potent biphalin analogues containing p-fluoro-l-phenylalanine at the 4,4′ positions and non-hydrazine linkers

Abstract

We report the synthesis and the biological evaluation of two new analogues of the potent dimeric opioid peptide biphalin. The performed modification is based on the replacement of two key structural elements of the native biphalin, namely: the hydrazine bridge which joins the two palindromic moieties and the phenylalanine residues at the 4,4′ positions of the backbone. The new analogues 9 and 10 contain 1,2-phenylenediamine and piperazine, respectively, in place of the hydrazidic linker and p-fluoro-L-phenylalanine residues at 4 and 4′ positions. Binding values are: Knormaliμ=0.51nM and Knormaliδ=12.8nM for compound 9, Knormaliμ=0.09nM and Knormaliδ=0.11nM for analogue 10.

Antinociceptive profile of potent opioid peptide AM94, a fluorinated analogue of biphalin with non‐hydrazine linker

“…In this sense, biphalin derivative AM94 is confirmed as a potent antinociceptive compound. The here reported results strongly support the rationale for design and synthesis of structurally modified analogs of biphalin , which do not present the toxicity connected with the presence of the hydrazine linker and are able to elicit, at the same time, the same analgesic effect of biphalin at lower doses.…”

“…The introduction of tertiary amide bonds, obtained by using a piperazine moiety as linker, resulted to be the most favorable substitution and led to analogs with higher affinity and stability . Encouraged by these results, a new fluorinated biphalin analogue, namely AM94 [(Tyr‐ d ‐Ala‐Gly‐pFPhe) 2 ‐piperazine], was synthesized (Figure ) . In this compound, the piperazine linker was combined with replacement of native residues of Phe in positions 4,4′ with residues of pFPhe.…”

“…This novel compound showed a μ‐opioid and δ‐opioid affinity at least tenfold higher than biphalin (Table ). Furthermore, guanosine triphosphate binding assay revealed an extremely high capacity to trigger the transduction mechanisms with an efficacy three to six times higher than biphalin for both μ and δ receptors . A subsequent in vivo evaluation in rats, performed by Leone et al , displayed that AM94 has a greater and more extended antinociceptive affect than biphalin in hot plate test, following both i.c.v and intravenous (i.v.)…”

“…The introduction of tertiary amide bonds, obtained by using a piperazine moiety as linker, resulted to be the most favorable substitution and led to analogs with higher affinity and stability [17]. Encouraged by these results, a new fluorinated biphalin analogue, namely AM94 [(Tyr-D-Ala-Gly-pFPhe) 2 -piperazine], was synthesized ( Figure 1) [18]. In this * Correspondence to: Adriano Mollica, Dipartimento di Farmacia, Università di Chieti-Pescara "G. d'Annunzio", Via dei Vestini 31, 66100 Chieti, Italy.…”

Potent Biphalin Analogs with µ/δ Mixed Opioid Activity: In Vivo and In Vitro Biological Evaluation

“…). Biphalin has been synthesized for the first time by Lipkowski et al and widely investigated by Hruby and coworkers . Its dimeric structure greatly enhances the analgesic activity and the duration of the antinociceptive effect with respect to enkephalins probably due to a cooperative binding and a better enzymatic stability .…”