Replacement of the peptide-backbone amides connecting Tyr-Gly and Gly-Gly in leucine-enkephalin with ketomethylene groups: synthesis and biological activity

Abstract

A peptide analogue of Leu-enkephalin was synthesized in which the amide linkages between Tyr-Gly and Gly-Gly were replaced by ketomethylene groups. The resulting analogue, 12, had 1/4000th and 1/2400th the opiate receptor binding activity of Leu-enkephalin when (3H) [D-Ala2,D-Leu5]enkephalin and (3H)naloxone, respectively, were used as tritiated ligands. When tested for analgesia in mice by the tail-flick assay, 12 produced analgesia in 50% of the mice tested at a dose of 24.3 micrograms/mouse (icv), while the ED50 of Leu-enkephalin is 240 micrograms/mouse (icv). At a dose of 40 micrograms/mouse (icv) or higher, 12 caused convulsions in a dose-dependent manner. No analgesia was observed after intravenous (iv) administration of 240 micrograms/mouse of 12.

Preparation and Evaluation at the Delta Opioid Receptor of a Series of Linear Leu-Enkephalin Analogues Obtained by Systematic Replacement of the Amides

“…13 20 +2.9 (c = 0.80, CHCl 3 ). Boc-Tyr(tBu)-Gly-OMe (General Protocol for Glycine Coupling) (28). H-Gly-OMe (1.11 g, 8.85 mmol) was dissolved in 1 M NaHCO 3 (50 mL) and extracted with DCM (3 × 50 mL).…”

“…15 All of the other replacements of amides have only been partial. Some replacements involve Nmethyl amides, 24 triazoles and tetrazoles (via click chemistry), 25 sulfonamides, 26 phosphonamidates, 27 ketomethylenes, 28 and retro-inverso amides. 29,30 Because the N-methyl amide and ester functions have the potential to act as hydrogen-bond acceptors and not as hydrogen-bond donors (Figure 1), 14 they can be introduced in peptides to mimic some properties of the amide bond and to study the roles of amide bonds in receptor binding and activity.…”

Efficient Synthesis of (S)-4-Phthalimido-1,3,4,5- tetrahydro-8-(2,6-dichlorobenzyloxy)-3-oxo-2H-2-benzazepin-2-acetic Acid (Pht-Hba(2,6-Cl2-Bn)-Gly-OH)1

“…Since glycine is the amino acid succeeding tyrosine in the sequence of HEL(52−61), we first tried to prepare the dipeptide Pht-Hba-Gly by the method described for the synthesis of the phenylalanine analogue Pht-Aba-Gly. − Accordingly, Pht-Tyr(Bn)-OH 1 (Scheme ) was converted to the acid chloride 2 using PCl 5 in benzene at 50−55 °C, and then reacted with glycine under the Schotten−Baumann conditions 12 to afford the dipeptide 3 in 73% yield. No racemization was detected during this reaction, as demonstrated by GITC derivatization after phthaloyl deprotection .…”

“…( S )- N α -Phthaloyl- O -benzyltyrosine Chloride (2). A solution of N α -Pht-Tyr(Bn)-OH 1 (1.01 g, 2.51 mmol) and PCl 5 (0.83 g, 4 mmol) in dry benzene (10 mL) was stirred at 50−55 °C for 90 min, and then the solvent was eliminated under reduced pressure. The residue was redissolved in dry benzene and evaporated.…”

Conformational restriction of the Tyr53 side‐chain in the decapeptide HEL[52‐61]: effects on binding to MHC‐II I‐Ak molecule and TCR recognition

“…2 (28). Compound 3 was converted to the corresponding acid chloride 4 , using PCl 5 in benzene at 50–55 °C (29), and then reacted with glycine under Schotten‐Baumann conditions (22) to afford the dipeptide 5 in 73% yield. No racemization was detected during this reaction, as demonstrated by GITC derivatization (30) after phthaloyl deprotection (31).…”