Analgesic dipeptide derivatives. 4. Linear and cyclic analogues of the analgesic compounds arginyl-2-[(o-nitrophenyl)sulfenyl]tryptophan and lysyl-2-[(o-nitrophenyl)sulfenyl]tryptophan.
The syntheses of Trp(Nps)-Arg-OMe.HCl (15) [Trp(Nps) = 2-[(o-nitrophenyl)sulfenyl]tryptophan], its three stereoisomers, and their corresponding cyclic analogues are reported. The preparation of Trp(Nps)-Lys-OMe (19) and its cyclic analogue is also described. All these compounds have been designed as analogues of the analgesic dipeptide derivatives X-Trp(Nps)-OMe (1b, X = Arg; 2b, X = Lys). In the case of dipeptides containing Arg or D-Arg, the coupling reactions were achieved via the isobutyl chloroformate and N-methylmorpholine mediated mixed anhydride procedure, while in the case of the Lys analogue, the N,N-dicyclohexylcarbodiimide method was employed. Sulfenylation reactions were carried out with Nps-Cl in acidic media. Cyclization to the diketopiperazines was achieved by using acetic acid as catalyst. The antinociceptive effects of all these new Trp(Nps)-containing dipeptides were evaluated after icv administration in mice, and the effects were compared with those of 1b, 2b, Tyr-Arg (Kyotorphin), and Tyr-D-Arg. The most active compounds, 15 and 19, were found to exhibit a naloxone-reversible antinociceptive effect similar to those of 1b and 2b and approximately 50 and 12.5 times higher than those of Kyotorphin and its D isomer, respectively. Trp(Nps)-D-Arg-OMe.HC1, D-Trp(Nps)-Arg-OMe.HC1, and cyclo[Trp(Nps)-Arg].HC1 were also more effective than Kyotorphin (5, 10, and 10 times, respectively). In view of the structure-activity relationships obtained, several similarities between this series of Trp(Nps)-containing dipeptides and that of Kyotorphin analogues have emerged.
Garcia-López
M T
MT
Instituto de Quimica Médica, CSIC, Madrid, Spain.
González-Muñiz
R
R
Molinero
M T
MT
Del Rio
J
J
D000700:Analgesics / Q000138:chemical synthesis* / Q000494:pharmacology; D000818:Animals; D004151:Dipeptides / Q000138:chemical synthesis* / Q000494:pharmacology; D004723:Endorphins / Q000494:pharmacology; D008297:Male; D051379:Mice; D008813:Mice, Inbred ICR; D013329:Structure-Activity Relationship
D000700:Analgesics; D004151:Dipeptides; D004723:Endorphins; C019448:kyotorphin; C049297:o-nitrophenylsulfenyl-lysyl-tryptophan