139551-74-9Relevant articles and documents
Exploration of the fifth position of leu-enkephalin and its role in binding and activating delta (DOP) and mu (MOP) opioid receptors
Ndong, Dominique Bella,Blais, Véronique,Holleran, Brian J.,Proteau-Gagné, Arnaud,Cantin-Savoie, Isabelle,Robert, William,Nadon, Jean-Fran?ois,Beauchemin, Sophie,Leduc, Richard,Pi?eyro, Graciela,Guérin, Brigitte,Gendron, Louis,Dory, Yves L.
, (2019)
Enkephalins are pentapeptidic endogenous ligands that regulate nociception by binding to mu (MOP) and delta (DOP) opioid receptors. To further explore the role of the leucine residue of Leu-enkephalin, 12 peptidomimetic analogs were synthesized by systematically replacing this residue with non-natural amino acids. The analogs were tested for their ability to bind DOP and MOP. We also investigated the potency of these analogs to inhibit cAMP production and to recruit β-arrestin 2 via both receptors. We found that replacement of the leucine residue by substituted non-natural amino acid derivatives of alanine, cycloleucine, or isoleucine was generally well tolerated. By contrast, substituting leucine with homoproline greatly reduced the affinity for DOP and, to a lesser extent, for MOP. Interestingly, when compared to Leu-enkephalin, analogs containing either aza-β-homoleucine or cycloleucine showed a bias toward inhibition of cAMP production through the activation of DOP but not MOP. By contrast, derivatives containing 4,5-dehydroleucine orD-allo-isoleucine conferred a bias toward β-arrestin 2 at MOP, but not DOP. Our results suggest that position 5 in Leu-enkephalin analogs can be further exploited to develop compounds with the potential to produce bias toward G protein or β-arrestin 2.
