title: Biphalin analogs containing β(3)-homo-amino acids at the 4,4' positions: Synthesis and opioid activity profiles.
abstract: Biphalin, a synthetic opioid octapeptide with a palindromic sequence has high analgesic activity. Biphalin displays a strong affinity for μ and δ-opioid receptors, and a significant to κ-receptor. The paper reports the synthesis of novel analogs of biphalin containing β(3)-homo-amino acid residues at the 4,4' positions and a hydrazine or 1,2-phenylenediamine linker. The potency and selectivity of the peptides were evaluated by a competitive receptor-binding assay in rat brain homogenate using [(3)H]DAMGO (a μ ligand) and [(3)H]DELT (a δ ligand). Analogs with β(3)-h-p-NO2Phe in positions 4 and 4' are the most active compounds. Selectivity depends on the degree of freedom between the two pharmacophore moieties. Analogs with a hydrazine linker show noticeable binding selectivity to μ receptors (IC50(μ)=0.72nM; IC50(δ)=4.66nM), while the peptides with a 1,2-phenylenediamine linker show slight δ selectivity (IC50(μ)=10.97nM; IC50(δ)=1.99nM). Tyr-d-Ala-Gly-β(3)-h-p-NO2PheNHNH-β(3)-h-p-NO2Phe (1) and (Tyr-d-Ala-Gly-β(3)-h-p-NO2PheNH)2 (2) produced greater antinociceptive effect compared to morphine after i.t. administration.
authors.affiliation: Institute of Organic Chemistry, Lodz University of Technology, Żeromskiego 116, 90-924 Lodz, Poland.
authors.forename: Oliwia
authors.initials: O
authors.lastname: Frączak
authors.affiliation: Institute of Organic Chemistry, Lodz University of Technology, Żeromskiego 116, 90-924 Lodz, Poland.
authors.forename: Anika
authors.initials: A
authors.lastname: Lasota
authors.affiliation: Mossakowski Medical Research Centre, Polish Academy of Sciences, Pawińskiego 5, 01-793 Warsaw, Poland.
authors.forename: Piotr
authors.initials: P
authors.lastname: Kosson
authors.affiliation: Mossakowski Medical Research Centre, Polish Academy of Sciences, Pawińskiego 5, 01-793 Warsaw, Poland.
authors.forename: Anna
authors.initials: A
authors.lastname: Leśniak
authors.affiliation: Mossakowski Medical Research Centre, Polish Academy of Sciences, Pawińskiego 5, 01-793 Warsaw, Poland.
authors.forename: Adriana
authors.initials: A
authors.lastname: Muchowska
authors.affiliation: Mossakowski Medical Research Centre, Polish Academy of Sciences, Pawińskiego 5, 01-793 Warsaw, Poland.
authors.forename: Andrzej W
authors.initials: AW
authors.lastname: Lipkowski
authors.affiliation: Institute of Organic Chemistry, Lodz University of Technology, Żeromskiego 116, 90-924 Lodz, Poland. Electronic address: aleksandra.olma@p.lodz.pl.
authors.forename: Aleksandra
authors.initials: A
authors.lastname: Olma
mesh_terms: D000596:Amino Acids / Q000737:chemistry*; D000701:Analgesics, Opioid / Q000138:chemical synthesis / Q000737:chemistry / Q000378:metabolism / Q000627:therapeutic use; D000818:Animals; D004745:Enkephalins / Q000138:chemical synthesis / Q000737:chemistry* / Q000378:metabolism / Q000627:therapeutic use*; D008297:Male; D010146:Pain / Q000188:drug therapy; D010455:Peptides / Q000138:chemical synthesis / Q000737:chemistry / Q000378:metabolism / Q000627:therapeutic use; D011485:Protein Binding; D051381:Rats; D017208:Rats, Wistar; D017465:Receptors, Opioid, delta / Q000378:metabolism
chemical_list: D000596:Amino Acids; D000701:Analgesics, Opioid; D004745:Enkephalins; D010455:Peptides; D017465:Receptors, Opioid, delta; C053673:biphalin
keywords: Antinociceptive potency; Biphalin analogs; Opioid peptides; α,β-Peptides; β(3)-Homo-amino acids