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Analgesic Dipeptides VI.: Synthesis and Structure‐Activity Relationships of N‐Terminal Modified Analogues of the Analgesic Compounds H‐Xaa‐Trp (Nps)‐OMe (Xaa=Lys, Orn, Arg)
Author(s) -
GarcíaLópez M. Teresa,
GonzálezMuñiz Rosario,
Harto Juan R.,
Molinero M. Teresa,
Río Joaquín Del
Publication year - 1989
Publication title -
archiv der pharmazie
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 0.468
H-Index - 61
eISSN - 1521-4184
pISSN - 0365-6233
DOI - 10.1002/ardp.19893220306
Subject(s) - chemistry , dipeptide , stereochemistry , analgesic , acetylation , diastereomer , acetic anhydride , chemical synthesis , peptide synthesis , peptide , organic chemistry , catalysis , biochemistry , in vitro , pharmacology , medicine , gene
In order to determine the influence of the N‐terminal amino group of the dipeptide derivatives H‐Xaa‐Trp [(Nps)‐OMe]Xaa=Lys ( 2a ), Orn ( 2b ), Arg ( 2c ) on their antinociceptive effects, the syntheses of their corresponding deaminated, acetylated and dimethylated analogues have been achieved. Deamino and dimethyl analogues of 2a , b , 6a , b , and 18a , b were prepared by coupling the corresponding N ω ‐Z‐ and N ω ‐Z‐N α ‐Me 2 amino acids with H‐Trp‐OMe, using the DCC/HOSu method, followed by sulfenylation of the resulting compounds and removal of the Z groups. Guanidylation of 6b and 18b provided the arginine analogues 6c and 18c , respectively. Ac‐Xaa‐Trp(Nps)‐OMe Xaa=Lys ( 11a ), Om ( 11b ) were synthesized by acetylation of H‐Xaa (Z)‐Trp (Nps)‐OMe with acetic anhydride, in the presence of 4‐dimethylaminopyridine, and subsequent removal of the Z groups. Coupling of Ac‐Arg‐OH‐HCl with H‐Trp‐OMe, using the DCC/HOSu procedure, followed by sulfenylation of the resulting 8:3 diastereomeric mixture of L, L and L, D dipeptides afforded Ac‐ ambo ‐Arg‐Trp(Nps)‐OMe 11c+11d . The antinociceptive effects of 6a – c , 11a – d , and 18a – c were evaluated after i.c.v. administration in mice. The N α ‐acetyl dipeptides 11 were found to exhibit a naloxone‐reversible antinociceptive effects comparable with those of 2 , while N‐deaminated and N, N ‐ dimethylated analogues were inactive.