Synthesis of linear and cyclic opioid‐based peptide analogs containing multipleN‐methylated amino acid residues

Abstract

A series of six novel opioid peptide analogs containing one to three N-methylamino acid residues, and six cyclic counterparts of these peptides were prepared by the solid-phase method. Introduction of two consecutive N-methylated amino acids, as well as cyclization of such conformationally constrained sequences, turned out to be challenging. The use of a recently reported triazine-based coupling reagent, 4-(4,6-dimethoxy-1,3,5-triazin-2-yl)-4-methylmorpholinium toluene-4-sulfonate, enabled the synthesis and cyclization of the designed analogs in acceptable yields and with a lesser amount of by-products than observed with the standard coupling reagents such as TBTU or HATU.

MEL-N16: A Series of Novel Endomorphin Analogs with Good Analgesic Activity and a Favorable Side Effect Profile

“…The residue at position 2 of the EMs is regarded as a key stereochemical spacer , These data further confirm that d -NMeAla 2 appears to be a favorable replacement for improving MOR activity. The results of the functional activity experiments paralleled those of the binding assays, with all of the compounds acting as full or partial agonists of the MOR and displaying high potencies.…”

“…For example, the Tyr 1 residue has been shown to play an important role in maintaining the physiological activity of opioid peptides, and the methylation of this tyrosine to 2,6-dimethyltyrosine (Dmt) effectively enhances the affinity of EMs for opioid receptors. , The Pro 2 residue of EMs is considered to be a linkage with stereochemical characteristics, and its main role is to limit the relative position of the pharmacophore in the peptide. The study of the degradation pathway of EMs has shown that Pro 2 is also an important restriction site. − Insertion of the noncyclic amino acid N -methyl- d -alanine ( d -NMeAla) is a transformation method that can reduce the stacking effect between peptide side-chain groups to provide a more potent peptide molecule. , Phe 4 can contribute to stabilizing the dominant conformation of polypeptide molecules. Furthermore, it not only plays an important role in maintaining the affinity of the peptides but also has a considerable effect on maintaining its selectivity. , Thus, modifying the key residues in the structures of the EMs is a feasible approach to developing analogs with improved properties. , …”

“…17−20 Insertion of the noncyclic amino acid Nmethyl-D-alanine (D-NMeAla) is a transformation method that can reduce the stacking effect between peptide side-chain groups to provide a more potent peptide molecule. 21,22 Phe 4 can contribute to stabilizing the dominant conformation of polypeptide molecules. Furthermore, it not only plays an important role in maintaining the affinity of the peptides but also has a considerable effect on maintaining its selectivity.…”

Synthesis, receptor binding studies, optical spectroscopic and in silico structural characterization of morphiceptin analogs with cis‐4‐amino‐L‐proline residues

“…Peptides were synthesized by a standard solid‐phase procedure, using Fmoc‐protected amino acids on MBHA Rink‐Amide resin (100–200 mesh, 0.6 mmol/g) as described earlier . Twenty percent piperidine in N,N ‐dimethylformamide (DMF) was used for deprotection of Fmoc‐groups, and O ‐(benzotriazol‐1‐yl)‐ N,N,N',N' ‐tetramethyluroniumtetrafluoroborate (TBTU) was employed as a coupling agent.…”

N‐methylation in amino acids and peptides: Scope and limitations

“…The standard and efficient coupling reagents N ‐[(1 H‐benzotriazol‐1‐yl)(dimethylamino)‐methylene]‐ N‐ methylmethanaminium tetrafluoroborate N‐ oxide (TBTU) and HATU are inefficient during the synthesis of opioid peptides, which are small cyclic peptides containing several NMAAs in a row . In contrast, the use 4‐(4,6‐dimethoxy‐1,3,5‐triazin‐2‐yl)‐4‐methylmorpholinium toluene‐4‐sulfonate (DMT/NMM/TsO ‐ ) as coupling reagent afforded the cyclic peptides in acceptable yields and trace amount of by‐products when compared to TBTU and HATU …”