title: Preparation and evaluation at the delta opioid receptor of a series of linear leu-enkephalin analogues obtained by systematic replacement of the amides.
abstract: Leu-enkephalin analogues, in which the amide bonds were sequentially and systematically replaced either by ester or N-methyl amide bonds, were prepared using classical organic chemistry as well as solid phase peptide synthesis (SPPS). The peptidomimetics were characterized using competition binding, ERK1/2 phosphorylation, receptor internalization, and contractility assays to evaluate their pharmacological profile over the delta opioid receptor (DOPr). The lipophilicity (LogD7.4) and plasma stability of the active analogues were also measured. Our results revealed that the last amide bond can be successfully replaced by either an ester or an N-methyl amide bond without significantly decreasing the biological activity of the corresponding analogues when compared to Leu-enkephalin. The peptidomimetics with an N-methyl amide function between residues Phe and Leu were found to be more lipophilic and more stable than Leu-enkephalin. Findings from the present study further revealed that the hydrogen-bond donor properties of the fourth amide of Leu-enkephalin are not important for its biological activity on DOPr. Our results show that the systematic replacement of amide bonds by isosteric functions represents an efficient way to design and synthesize novel peptide analogues with enhanced stability. Our findings further suggest that such a strategy can also be useful to study the biological roles of amide bonds.
authors: Département de Physiologie et Biophysique, Institut de Pharmacologie, Université de Sherbrooke , 3001, 12e Avenue Nord, Sherbrooke, Québec J1H 5N4, Canada.
authors: Kristina
authors: K
authors: Rochon
authors: Arnaud
authors: A
authors: Proteau-Gagné
authors: Philippe
authors: P
authors: Bourassa
authors: Jean-François
authors: JF
authors: Nadon
authors: Jérome
authors: J
authors: Côté
authors: Véronique
authors: V
authors: Bournival
authors: Fernand
authors: F
authors: Gobeil
authors: Brigitte
authors: B
authors: Guérin
authors: Yves L
authors: YL
authors: Dory
authors: Louis
authors: L
authors: Gendron
mesh_terms: D000577:Amides / Q000494:pharmacology; D000818:Animals; D047630:Depsipeptides / Q000138:chemical synthesis / Q000494:pharmacology; D004743:Enkephalin, Leucine / Q000031:analogs & derivatives* / Q000138:chemical synthesis; D004952:Esters / Q000138:chemical synthesis / Q000494:pharmacology; D006860:Hydrogen Bonding; D008297:Male; D051379:Mice; D057786:Peptidomimetics / Q000138:chemical synthesis / Q000494:pharmacology*; D017465:Receptors, Opioid, delta / Q000187:drug effects / Q000378:metabolism*; D060327:Solid-Phase Synthesis Techniques / Q000379:methods; D014649:Vas Deferens / Q000187:drug effects
chemical_list: D000577:Amides; D047630:Depsipeptides; D004952:Esters; D057786:Peptidomimetics; D017465:Receptors, Opioid, delta; D004743:Enkephalin, Leucine
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