- Exploration of the fifth position of leu-enkephalin and its role in binding and activating delta (DOP) and mu (MOP) opioid receptors
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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.
- 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.
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- Syntheses of racemic and non-racemic silicon- and germanium-containing α-amino acids of the formula type H2NCH(CH2ElR3)COOH (El=Si, Ge; R=organyl) and incorporation of D-H2NCH(CH2SiMe3)COOH and D-H2NCH(CH2GeMe3)COOH into biologically active decapeptides: A study on C/Si/Ge bioisosterism
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Two novel efficient methods for the synthesis of racemic silicon- and germanium-containing α-amino acids of the formula type rac-H2NCH(CH2ElR3)COOH (El=Si, Ge; R=organyl), starting from 3,6-diethoxy-2,5-dihydropyrazine, have been developed. Racemic α-amino acids synthesized: rac-H2NCH(CH2SiMe3)COOH (rac-2), rac-H2NCH(CH2GeMe3)COOH (rac-3), rac-H2NCH(CH2SiMe2Ph)COOH (rac-4), rac-H2NCH(CH2GeMe2Ph)COOH (rac-5), and rac-H2NCH(CH2SiMe2CH=CH2)COOH (rac-6). Preparative liquid-chromatographic resolution of rac-2 and rac-3 [CHIROBIOTIC T (glycopeptide Teicoplanin covalently linked to spherical silica gel) as the stationary phase] yielded the α-amino acids (R)-2, (S)-2, (R)-3, and (S)-3. The (R)- and (S)-enantiomers of β-(trimethylsilyl)alanine [(R)- and (S)-2] and β-(trimethylgermyl)alanine [(R)- and (S)-3] are sila-analogs and germa-analogs, respectively, of the antipodes of the non-proteinogenic α-amino acid β-tert-butylalanine [(S)- and (R)-H2NCH(CH2CMe3)COOH; (S)- and (R)-1]. Starting from the N-Fmoc-protected C/Si/Ge-analogous (D-configurated) α-amino acids (R)-1, (S)-2, and (S)-3, the C/Si/Ge-analogous decapeptides 7-9 [Ac-D-Nal1-4-Cl-D-Phe2-D-Pal3-Ser 4-N-Me-Tyr5-D-Hci6-Nle7-Arg 8-Pro9-D-Me3El-Ala10-NH2 (7, El=C; 8, El=Si; 9, El=Ge)] were prepared by sequential solid-phase synthesis. The decapeptides 7-9 were studied in vitro in a functional assay using a recombinant cell line expressing the human GnRH receptor (agonist Triptorelin). Compounds 7-9 behaved as medium-potent GnRH antagonists, the antagonistic potencies of these three C/Si/Ge analogs being very similar.
- Merget, Markus,Günther, Kurt,Bernd, Michael,Günther, Eckhard,Tacke, Reinhold
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p. 183 - 194
(2007/10/03)
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