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)
✍ Scribed by M. Teresa García-López; Rosario González-Muñiz; Juan R. Harto; M. Teresa Molinero; Joaquín Del Río
- Book ID
- 102749269
- Publisher
- John Wiley and Sons
- Year
- 1989
- Tongue
- English
- Weight
- 613 KB
- Volume
- 322
- Category
- Article
- ISSN
- 0365-6233
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✦ Synopsis
In order to determine the influence of the N-terminal amino group of the dipeptide derivatives H-Xaa-Trp@ps)-OMe[Xaa=Lys (2a). Om (2b). Arg
( 2 4 on their antinociceptive effects, the syntheses of their cmponding deaminated. acetylated and dimethylated analogues have been achieved. Deamino and dimethyl analogues of 2a,b, Q,b, and 18n,b were prepared by coupling the corresponding N"-2-and N'"-Z-Na-Mq amino acids with H-TpOMe, using the DCC/HOSu m e t h a followed by sulfenylation of the resulting compounds and removal of the 2 groups. Guanidylation of 6b and 18b provided the arginine analogues 6c and 18c, respectively. Ac-Xaa-Trp(Nps)-OMe [Xaa=Lys (lla), Om (llb) were synthesized by acetylation of H-Xaa( )-Trp(Nps)-OMe with acetic anhydride, in the presence of 4dimethylaminopyridine, and subsequent removal of the 2 groups. Coupling of Ac-Arg-OH.HC1 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-&-Arg-Trp(Nps)OMe llcclld. The antinociceptive effects of Q-c, llad, and 18 a-c were evaluated after i.c.v. administration in mice. TIE P-acetyl dipeptides 11 wee found to exhibit a naloxone-reversible antinociceptive effects comparable with those of 2, while N-deaminated and N, Ndimethylated analogues were inactive. Dipeptide als Analgetika, 6.Mitt: Synthese und SAR-Studien an N-termind modifuierten Analogs des Analgeticums H-Xaa-Trp(Nps)-OMe (Xaa=Lys, Om, Arg). Mil der Absichk den EinfluS der Endaminogruppe der Dipeptidverbindungen H-Xaa-Trp(Nps)-OMe [Xaa=Lys ( 2 ~) . Om (Zb), Arg ( 2 4 auf ihre antinociceptive Whung zu priifen, wurden die entspr. deaminierten, acetylienen und dimethylierten Analoga synthetisien. Die Deaminound Dimethylverbindungen von 2a,b, 64b und 1&,b wurden i l k die Kupplung der entspr. NO-2und NO-ZN =-Me2 a m i n o s h n mit H-TrpOMe unter Anwendung der DCC/HOSu Methode mit anschlieknder Sulfenylierung da erhaltenen Verbindungen und letzlich Ahspaltung der z-Gruppen synthetisiert. Guanidylierung von Q und 18b fiihrle zu den Argininanaloga 6c bnv. 18c. Ac-Xaa-Trp(Nps)-OMe [Xaa=Lys (lla), Om (llb)] wurden durch Acetylierung von H-Xaa(Z)-Trp(NpstOMe mit Essigs%ureanhydrid&Dimethylaminopyridin und anschlieknde Abspaltung der ZGNppen emalten Die Kupplung von Ac-Arg-OH.