Deltorphin II Analogues with 6-Hydroxy-2-aminotetralin-2-carboxylic Acid in Position 1

Abstract

Two approaches to the design of very active and highly selective delta opioid peptides were used to obtain new deltorphin analogues with altered hydrophobic and stereoelectronic properties. Deltorphin II analogues were synthesized with the substitution of Ile instead of Val at positions 5 and 6 in the address domain and 6-hydroxy-2-aminotetralin-2-carboxylic acid (Hat) instead of Tyr(1) in the message domain. In the radioreceptor-binding studies, in which type-specific tritiated opioid ligands were used, (R)- and (S)-Hat-deltorphins exhibited similar K(i) values, revealing high delta selectivity. The peptides displayed agonist properties in the in vitro bioassay, with IC(50) values in the subnanomolar range in the mouse vas deferens assay and in the micromolar or higher range in the guinea pig ileum assay, again demonstrating a high selectivity toward delta receptors. The agonist property of the new ligands was confirmed by means of [(35)S]GTPgammaS-binding experiments in membranes of the rat frontal cortex.

Effect of chronic intra‐peritoneally administered chimeric peptide of met‐enkephalin and FMRFa‐[d‐Ala2]YFa‐on antinociception and opioid receptor regulation

“…A similar δ receptor specificity was reported for other peptide agonists which either contained d ‐alanine amino acid or other d ‐amino acid residues at second position, e.g. deltorphin I (Tyr‐ d ‐Ala‐Phe‐Asp‐Val ‐Val‐Gly‐NH 2 ), deltorphin II (Tyr‐ d ‐Ala‐Phe‐Glu‐Val ‐Val‐Gly‐NH 2 ) and DADLE [ d ‐Ala 2 , d ‐Leu 5 ]‐enkephalin, dermenkephalin (Tyr‐ d ‐Met‐Phe ‐His‐Leu‐Met‐Asp‐NH 2 ), DSLET[ d ‐Ser 2 , Leu 5 ]‐enkephalin and DPDPE [ d ‐Pen 2 , d ‐Pen 5 ]‐enkephalin (Akiyama et al, 1985; Amiche et al, 1989; Broccardo and Improta, 1992; Cheng et al, 1993; Darula et al, 2000; David et al, 1982; Erspamer et al, 1989; Jiang et al, 1991).…”

“…Phe -His-Leu-Met-Asp-NH 2 ), DSLET[D-Ser 2 , Leu 5 ]-enkephalin and DPDPE [D-Pen 2 , D-Pen 5 ]-enkephalin (Akiyama et al, 1985;Amiche et al, 1989;Broccardo and Improta, 1992;Cheng et al, 1993;Darula et al, 2000;David et al, 1982;Erspamer et al, 1989;Jiang et al, 1991).…”

Synthesis and biological evaluation of constrained analogues of the opioid peptide H‐Tyr‐d‐Ala‐Phe‐Gly‐NH2 using the 4‐amino‐2‐benzazepin‐3‐one scaffold

“…A similar investigation of restraining the conformational flexibility of the Tyr 1 and Phe 3 side chains in deltorphin II, by introducing a 4‐aminobenzazepinone scaffold as well as by using 1,2,3,4‐tetrahydroisoquinoline‐3‐carboxylic acid (Tic), 2‐aminotetralin‐2‐carboxylic acid (Atc), 6‐hydroxy‐2‐aminotetralin‐2‐carboxylic acid (Hat) and 2‐aminoindan‐2‐carboxylic acid (Aic), resulted in high δ ‐selectivity for those analogues that can adopt a trans side chain conformation (6,9,10).…”

Side Chain Cyclized Aromatic Amino Acids: Great Tools as Local Constraints in Peptide and Peptidomimetic Design

“…Upon substitution of Tyr in sequence 151 (Figure 27) with (R)-and (S)-6-HO-Atc, similar K i values to the native ligand, high DOR selectivity, and potent agonist responses were observed. 151 From NMR analysis of these peptides, the preferred gauche (−) and gauche (+) conformations for (S)-and (R)-6-HO-Atc, respectively, could be assigned unambiguously (Figure 32). Similarly, when the Phe residue in the message domains of 151 was replaced by the (S)-or (R)-Atc residues, subnanomolar DOR agonists were obtained.…”