Analgesic Dipeptide Derivatives. 3. Synthesis and Structure-Activity Relationships of o-Nitrophenyl-Modified Analogues of the Analgesic Compound H-Lys-Trp(NPS)-OMe

Article abstract of DOI:10.1021/jm00392a023

A series of analogues of the analgesic dipeptide derivative H-Lys-Trp(NPS)-OMe has been designed to determine the influence of the (2-nitrophenyl)sulfenyl (NPS)moiety on the activity.The syntheses and antinociceptive effects of these analogues of general formula H-Lys-Trp(R)-OMe sulfenyl (AacCmES) (13); R = <2-(acetylamino)phenyl>sulfenyl (AacPS) (17); R = tert-butylsulfenyl (t-BuS) (23); R = (2-carbomethoxyethyl)sulfenyl (CmES) (24)> are described.Reaction of Z-Lys(Z)-Trp-OMe (3) with PS-, CmPS-, pNPS-, DNPS-, and AacCmES-Cl afforded the corresponding 2-(sulfenyl)tryptophan derivatives, which on treatment with boron-tris(trifluoroacetate)/trifluoroacetic acid or trimethylsilyl iodide in acetonitrile (Me3SiI/CH3CN) provided 9-13, respectively.Sulfenylation of 3 with NPS-Cl gave Z-Lys(Z)-Trp(NPS)-OMe, which, on catalytic hydrogenation of the nitro group using 10percent Pd/C followed by acetylation of the resulting amino function and removal of the protecting Z group, gave 17.Condensation of 2-(ter-butylsulfenyl)- and 2-<(2-carbomethoxyethyl)sulfenyl>tryptophan methyl ester, obtained by reaction of methyl 3a -hydroxy-1,2,3,3a,8,8a-hexahydropyrrolo<2,3-b>indole-2-carboxylate with the corresponding thiol, with Z-Lys(Z)-OSu afforded Z-Lys(Z)-Trp(t-BuS)-OMe and Z-Lys(Z)-Trp(CmES)-OMe, which on treatment with Me3SiI/CH3CN provided 23 and 24, respectively.Intracerebroventricular administration of 10 elicited a naloxone-reversible antinociceptive effect in mice similar to that of H-Lys-Trp(NPS)-OMe.No analgesia was however found with the phenylsulfenyl or acyclic sulfenyl substituted dipeptides 9, 11, and 17 or 13, 23, and 24.The Trp(DNPS)-containing analogue was neurotoxic.Structure-activity studies indicate that the role of the NPS and CmPS moieties could be related to the adoption of a preferential active conformation.