Conformationally Constrained Deltorphin Analogs with 2-Aminotetralin-2-Carboxylic Acid in Position 3

Abstract

Two approaches to the design of very active and highly selective delta opioid peptides were used to obtain new deltorpin analogs with altered hydrophobic and stereoelectronic properties. Deltorphin I and II analogs were synthesized involving the substitution of Ile instead of Val at positions 5 and 6 in the address domain and 2-aminotetralin-2-carboxylic acid (Atc) instead of Phe in the message domain. The peptides were agonists in the subnanomolar range in the MVD assay and in the micromolar or higher range in the GPI assay, showing a very high selectivity for delta receptors. A very similar trend could be observed in radioreceptor binding assays in which selective tritiated opioid ligands were used. (R)- and (S)-Atc-deltoriphins exhibited similar Ki values in the binding assay, with almost complete loss of the stereospecificity of the binding. Conformational studies provided evidence for the little disturbance of the backbone conformational equilibrium when Phe3 is replaced by (S)- or (R)-Atc. The use of the Atc constraint gives additional evidence that, during its interaction with the delta receptor, the side chain of residue 3 adopts the trans conformation at chi 1.

Direct chiral separation of unnatural amino acids by high‐performance liquid chromatography on a ristocetin a‐bonded stationary phase

“…The names of the investigated compounds, nomenclature, and abbreviations are in accordance with the IUPAC-IUB JCBN recommendation. 34,35 The synthesis of 2Ј-methylphenylalanine (7; 2-MePhe), 36 4Ј-methylphenylalanine (8; 4-MePhe), 3 7 2Ј,6Јdimethylphenylalanine (9; 2,6-diMePhe), 36 The following analytes were synthesized as racemates: erythro-(2S,3S and 2R,3R)-␤-methylphenylalanine (11; erythro-␤-MePhe), 3 9 threo-(2S,3R and 2R,3S)-␤methylphenylalanine (12; threo-␤-MePhe), 39 2Ј,6Јdimethyltyrosine (2; 2 ,6 -diMeTyr), 4 0 2 Ј ,6Јdimethyltyrosineamide (3; 2,6-diMeTyrNH 2 ), 41 erythro-(2S,3S and 2R,3R)-␤-methyltyrosine (5; erythro-␤-MeTyr), 42 threo-(2S,3R and 2R,3S)-␤-methyltyrosine (6; threo-␤-MeTyr), 42 1,2,3,4-tetrahydroisoquinoline-1carboxylic acid (13; Tic1), 4 3 6Јhydroxy-1,2,3,4tetrahydroisoquinoline-3-carboxylic acid (15; 6-HO-Tic3), 38 erythro-(2S,3S and 2R,3R)-4-methyl-1,2,3,4tetrahydroisoquinoline-3-carboxylic acid (19; erythro-␤-MeTic3), 38 threo-(2S,3R and 2R,3S)-4-methyl-1,2,3,4tetrahydroisoquinoline-3-carboxylic acid (20; threo-␤-MeTic3), 38 2-aminotetralin-2-carboxylic acid (21; Atc), 44 6-hydroxy-2-aminotetralin-2-carboxylic acid (22; Hat), 45 6-methoxy-2-aminotetralin-2-carboxylic acid (23; MeO-Atc), 45 erythro-(2S,3S and 2R,3R)-␤-methyltryptophan (24; erythro-␤-MeTrp), 4 6 threo-(2S,3R and 2R,3S)-␤methyltryptophan (25; threo-␤-MeTrp). 46 The physicochemical data of amino acids synthesized were determined and were identical with the data cited in references 36-46, respectively, except for analyte 3.…”

Rational Approach to the Design of Bioactive Peptidomimetics: Recent Developments in Opioid Agonist Peptides

“…It is well established that d-opiate receptors prefer more compact structures while linear conformationally peptides, e.g., dermorphin are -opiate agonists [34]; amino acids in the fifth and the sixth positions preserve the affinity and selectivity of Ala-deltorphins and in general these two properties are enhanced in peptide analogs with more hampered aliphatic portion of the side chains [35].…”

Conformational constraints in angiotensin IV to probe the role of Tyr2, Pro5 and Phe6

“…As part of our ongoing studies on the role of the individual amino acid residues an Ang IV, while studying the inhibition of IRAP activity rather than the binding to the apo‐enzyme as was done in previous studies26–30, we now report the results of the modification of Tyr 2 , Pro 5 and Phe 6 . Introducing conformationally, constrained amino acids in a peptide has been shown to be a powerful method to confer selectivity and stability31–40. Constraints may eventually improve potency by reducing the entropy change during binding to the active site of a receptor or enzyme, and may also lead to increased metabolic stability and selectivity41.…”