- Helix-inducing α-aminoisobutyric acid in opioid mimetic deltorphin C analogues
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The achiral symmetric α-aminoisobutyric acid (Aib) replaced the critical N-terminal residues of the amphibian skin opioid deltorphin C (H- Tyr-D-Ala-Phe-Asp-Val-Val-Gly-NH2) without detriment to the physicochemical requirements for δ opioid receptor recognition. Substitutions by the α,α- dialkyl amine acid in place of D-Ala2 or Phe8, or both, exhibited high δ receptor affinity (Kiδ = 0.12-3.6 nM) and 5-9-fold greater selectivity (K(i)μ/K(i)δ = 5000-8500) than the parent compound. This is the first definitive demonstration that the D-chirality of alanine and the aromaticity of phenylalanine are replaceable by an achiral α,α-dialkylated residue without detrimental effects on ligand binding. Incorporation of the mono-α- alkyl amino acid L- or D-Ala, at the third position also produced highly selective δ ligands (K(i)μ/K(i)δ = 2000-3500), albeit with reduced δ affinities (K(i)δ = 6-15 nM). Replacement of the anionic residue Asp4 by Aib yielded an opioid peptide that fit two-site binding models for the δ receptor (η = 0.763; P 2, Asp4, and simultaneously D-Ala2 and Phe3 but not when substituted for Phe3. These conformational changes might be critical factors for the proper orientation of reactive constituents of residues in the N-terminal region of deltorphin C. Disparities between binding data and functional bioassays of [Aib3] indicated that Phe3 was required for bioactivity in mouse vas deferens but not for interaction with δ opioid receptors in rat brain membranes.
- Bryant, Sharon D.,Guerrini, Remo,Salvadori, Severo,Bianchi, Clementina,Tomatis, Roberto,Attila, Martti,Lazarus, Lawrence H.
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- Probing the stereochemical requirements for receptor recognition of δ opioid agonists through topographic modifications in position 1
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A series of side-chain constrained tyrosine derivatives, 2',6'-dimethyl-β-methyltyrosines (TMT), has been designed and incorporated into position 1 of the highly selective δ opioid agonists DPDPE (Tyr-D-Pen2-Gly-Phe-D-Pen5-OH) and deltorphin I (DELT I, Tyr-D-Ala-Phe-Asp-Val-Val-Gly-NH2). Molecular mechanics calculations on isolated TMT residues and nuclear magnetic resonance (NMR) studies of the TMT1-containing peptides in DMSO showed that each of the four stereoisomers of TMT favors one particular rotamer of the side-chain χ1 torsional angle. Therefore, substitution of four TMT isomers for Tyr1 allows us to perform a systematic conformational scan through three staggered rotamers of the aromatic side chain, gauche (-), trans, and gauche (+), and to explore specific binding requirements of the receptor in relation to the side chain conformation. The potency and selectivity of four isomers of [TMT1]DPDPE and four isomers of [TMT1]DELT I were evaluated by radioreceptor binding assays in the rat brain using μ- and δ-selective radiolabeled ligands and by bioassays with guinea pig ileum (GPI, μ receptor) and mouse vas deferens (MVD, δ receptor). In the DPDPE series only one isomer, [(2S,3R)-TMT1 ]DPDPE showed high potency and selectivity for the δ opioid receptors. The favorable side-chain rotamers found for this analogue, i.e., the trans rotamer of TMT1 and the gauche (-) rotamer of Phe4, were proposed as the most probable δ receptor-binding conformations of DPDPE analogues. Two [TMT1]DELT I isomers possessed considerable δ receptor potencies. The (2S,3R)-TMT1 isomer appeared to be a superpotent, but moderately δ-selective agonist, while the (2S,3S)-TMT1 isomer showed the highest selectivity for the δ receptors in this series. Surprisingly, [(2R,3R)TMT1]DELT I also was moderately potent at the δ receptor. These results suggest that the δ receptor requirements for the linear DELT I analogues may be satisfied with two different modes of binding of the (2S,3S)- and (2S,3R)TMT1 isomers. This study provides important guidance for the design of peptide and non-peptide ligands selective for the δ opioid receptor.
- Qian,Shenderovich,Kover,Davis,Horvath,Zalewska,Yamamura,Porreca,Hruby
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- A rapid and efficient synthesis of the δ-opioid agonist, deltorphin
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A rapid and efficient solid phase synthesis of the δ-receptor selective opioid peptide, deltorphin has been accomplished by a new methodology using 9-fluorenylmethyloxycarbonyl-amino acid chloride, triethylamine and 1-hydroxybenzotriazole, the solid suppo
- Sivanandaiah, K. M.,Babu, V. V. Suresh,Renukeshwar, H. C.,Gangadhar, B. P.
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p. 465 - 467
(2007/10/02)
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- Unique sequence in deltorphin C confers structural requirement for δ opioid receptor selectivity
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A series of deltorphin C (H-Tyr-D-Ala-Phe-Asp-Val-Val-Gly-NH2) analogues were synthesized to assess the consequences of changing anionic and hydrophobic residues on δ receptor selectivity.Analogues with altered C-terminal groups, inverted sequences, or es
- Lazarus, LH,Salvadori, S,Grieco, P,Wilson, WE,Tomatis, R
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p. 791 - 797
(2007/10/02)
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- Conformationally Restricted Deltorphin Analogues
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Conformationally restricted deltorphin analogues were synthesized either through incorporation of cyclic phenylalanine analogues in position 2 or 3 of the peptide sequence or through various side chain-to-side chain cyclizations.Compounds were tested in μ-, δ-, and κ-receptor selective binding assays and in the guinea pig ileum (GPI) and mouse vas deferens (MVD) bioassays.Replacement of Phe3 in 2>deltorphin I with 2-aminoindan-2-carboxylic acid (Aic) or L- or D-2-aminotetralin-2-carboxylic acid (Atc) resulted in agonist compounds which retained the high δ receptor selectivity of the parent peptide.Substitution of a tetrahydroisoquinoline-3-carboxylic acid (Tic) residue in the 2-position of 2>deltorphin I and 4,Nle6>deltorphin produced a partial δ agonist, H-Tyr-Tic-Phe-Asp-Val-Val-Gly-NH2, and a pure δ antagonist, H-Tyr-Tic-Phe-Phe-Leu-Nle-Asp-NH2, respectively.The later antagonist displayed high δ selectivity (Kiμ/Kiδ=502) and was a potent antagonist against selective δ agonists in the MVD assay (Ke ca. 10 nM).Various 2>-deltorphin I analogues cyclized between the side chains of Orn (or Lys) and Asp (or Glu) residues substituted in positions 2 and 4, 4 and 7, and 2 and 7 were essentially nonselective.Comparison with corresponding N-terminal tetrapeptide analogues revealed that the C-terminal tripeptide segment in the deltorphin heptapeptides made a crucial contribution to δ affinity and δ selectivity in the case of the agonist peptides but not in the case of the antagonist.
- Schiller, Peter W.,Weltrowska, Grazyna,Nguyen, Thi M.-D.,Wilkes, Brian C.,Chung, Nga N.,Lemieux, Carole
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p. 3956 - 3961
(2007/10/02)
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