A novel dermorphin tetrapeptide N(alpha)-amidino-Tyr-D-Arg-Phe-MebetaAla-OH (ADAMB) was designed based on the structures of several dermorphin tetrapeptide analogues, including N(alpha)-amidino-Tyr-D-Arg-Phe-Gly-OH (ADA-DER), H-Tyr-D-Arg-Phe-betaAla-OH (TAPA), and H-Tyr-D-Arg-Phe-Sar-OH (DAS-DER). These parent compounds were known to show a weak oral analgesic activity in animals and/or to possess a different mechanism of analgesia from other mu-opioid peptides. Six analogues of ADAMB were also synthesized to investigate the effect on potency of N-terminal amidination and N-methyl-beta-alanine (MebetaAla) substitution at position 4. Compounds were assessed using the tail pressure test in mice after subcutaneous and oral administration. Among the peptides tested, ADAMB showed the strongest oral antinociceptive activity, with an ED(50) of 5.8 vs 22.2 mg/kg for morphine, as well as a 38-fold stronger activity after subcutaneous administration. ADAMB also showed long-lasting antinociceptive activity, with 50% of the maximum effect persisting in the tail pressure test at 10 h after oral administration (10 mg/kg). In contrast, orally administered morphine (80 mg/kg) showed a rapid decrease of activity in the same test and its antinociceptive effect disappeared within 4 h. When the antinociceptive effect of ADAMB was compared with that of analogues possessing betaAla(4) (1) or Sar(4) (2), as well as analogues with N-substitution (3-6), it was found that both the N(alpha)-amidino substitution and the MebetaAla(4) were synergistically involved in creating ADAMB's exceptionally high antinociceptive activity.
To improve the oral bioavailability of a dermorphin tetrapeptide analog, N(alpha)-1-iminoethyl-Tyr-D-MetO-Phe-MebetaAla-OH (III), which has a potent analgesic activity after oral administration, various derivatives were synthesized to increase lipophilicity by esterification of the C-terminal carboxyl group and/or acylation of the phenolic hydroxyl group on Tyr1. Antinociceptive activity was evaluated after subcutaneous or oral administration using the mouse tail pressure test. As a result, increased antinociceptive activity after oral administration as well as an improved ED50(p.o.)/ED50(s.c.) ratio, which is an indicator of oral bioavailability, were found for some compounds. With regard to the improvement of bioavailability, derivatives with acylation of the phenolic hydroxyl group on Tyr1 showed better results than derivatives with esterification of the C-terminal carboxyl group. In particular, an ED50(p.o.)/ED50(s.c.) ratio equivalent to that of morphine was found for an acetylated derivative, N(alpha)-1-iminoethyl-Tyr(COMe)-D-MetO-Phe-MebetaAla-OH (7a), as well as for a methoxycarbonylated derivative, N(alpha)-1-iminoethyl-Tyr(CO2Me)-D-MetO-Phe-MebetaAla-OH (7l).
[reaction: see text] A new and versatile 4-alkoxy-2-hydroxybenzaldehyde (AHB) linker for solid-phase syntheses is described. Acylation of the polymer-bound secondary amine obtained from reductive amination of the aldehyde in the AHB linker showed good reactivity. Following acylation of the phenolic hydroxyl group, the resulting carboxamide resin was stable to treatment with 95% TFA. The O-acyl functional group was removed with 20% piperidine and the desired compound was cleaved from the resin by TFA treatment.
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