122752-15-2Relevant articles and documents
Helix-inducing α-aminoisobutyric acid in opioid mimetic deltorphin C analogues
Bryant, Sharon D.,Guerrini, Remo,Salvadori, Severo,Bianchi, Clementina,Tomatis, Roberto,Attila, Martti,Lazarus, Lawrence H.
, p. 2579 - 2587 (1997)
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.
A rapid and efficient synthesis of the δ-opioid agonist, deltorphin
Sivanandaiah, K. M.,Babu, V. V. Suresh,Renukeshwar, H. C.,Gangadhar, B. P.
, p. 465 - 467 (2007/10/02)
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
Conformationally Restricted Deltorphin Analogues
Schiller, Peter W.,Weltrowska, Grazyna,Nguyen, Thi M.-D.,Wilkes, Brian C.,Chung, Nga N.,Lemieux, Carole
, p. 3956 - 3961 (2007/10/02)
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.
