Pharmacological profile and molecular modeling of cyclic opioid analogs incorporating various phenylalanine derivatives.

: Peptide-based agonists of the µ opioid receptor (µOR) are promising therapeutic candidates for pain relief with reduced side effects compared to morphine. A deep understanding of µOR-ligand interactions is necessary for future design of peptide-based opioid analgesics. To explore the requirements of the µOR binding pocket, eight new analogs of our cyclic peptide Tyr-c[D-Lys-Phe-Phe-Asp]NH 2 displaying high µOR affinity were synthesized, in which Phe in either third or fourth position was replaced by various derivatives of this amino acid (β 3 -Phe, homoPhe, β 3 -homoPhe and PhGly). The aim of this research was to examine structural effects of such modifications on the bioactivity and both, experimental and theoretical methods were used. The binding of the cyclic analogs to all three OR types (µ, δ, κ) was assessed by radioligand competitive binding assay and their functional activity was determined by calcium mobilization assay. In order to provide structural hypotheses explaining the obtained experimental affinities, the complexes of the cyclic peptides with μOR were subjected to molecular modeling.