78981-81-4Relevant academic research and scientific papers
Study of intramolecular aminolysis in peptides containing N-alkylamino acids at position 2
Ryakhovsky, Vladimir V.,Ivanov, Andrey S.
supporting information; experimental part, p. 7070 - 7076 (2012/08/29)
Many peptides and proteins, containing Nα-alkylamino acids (including proline) at the second position, are prone to intramolecular aminolysis (IA) with elimination of N-terminal dipeptide sequence as 2,5-diketopiperazines (DKP). We synthesized a series of short peptides, containing N-alkylamino acids at position 2, and studied their stability in the presence of acetic acid and amines. The presence of side chains in the second and the third amino acid residues and alkylation at Nα of the third amino acid residue slowed down IA. Nα-Alkyl residue in the first amino acid residue impeded IA only in peptides, containing three or more residues. Side chains of the first amino acids did not affect significantly the cleavage rates. Acetic acid promoted IA more strongly than aqueous ammonia, while tertiary amines were less effective. Peptides with methionine-S-oxide residues were more labile than the unoxidized analogs, suggesting intramolecular assistance of the S-oxide group in aminolysis. Surprisingly, intermediate compounds of the formula Boc-Met-MeXaa-Sar-NHR underwent rapid cleavage (endopeptolysis) upon attempted acidolytic deprotection.
Peripherally Acting Enkephalin Analogues. 2. Polar Tri- and Tetrapeptides
Hardy, George W.,Lowe, Lawrence A.,Mills, Gail,Sang, Pang Yih,Simpkin, Dean S. A.,et al.
, p. 1108 - 1118 (2007/10/02)
The design, synthesis, and biological activity of a series of -Arg2-enkephalin-derived tetrapeptide amides and tripeptide aralkylamides are reported.These polar analogues were designed to be excluded from the central nervous system with their action thus limited to peripheral opioid receptors.The effects of the nature of the aromatic ring, aryl ring substitution, and aralkylamine chain length on activity were investigated; in a number of cases the N-terminal amino group of Tyr1 was converted to a guanidino group to further increase hydrophilicity.The peptides were all synthesized by classical solution methodology.The opioid activit y of the peptides was assessed in vitro on the guinea pig ileum and their antinociceptive activity was determined in vivo in chemically induced writhing models (peripheral activity) and in the hot-plate test (central activity), in rodents.That the analgesic effects were predominantly mediated in the periphery was demonstrated by antagonism of antinociception by the peripheral opioid antagonist N-methylnalorphine and by comparison of the activities in the writhing and hot-plate tests.As a class, the tetrapeptides were more potent than the tripeptides; Nα-amidination generally increased activity.A number of compounds exhibited very potent opioid activity and had the desired pharmacological profile, indicating a high degree of peripheral selectivity.
