Synthesis and Structure−Activity Relationships of an Orally Available and Long-Acting Analgesic Peptide, Nα-Amidino-Tyr-d-Arg-Phe-MeβAla-OH (ADAMB)

A novel dermorphin tetrapeptide Nα-amidino-Tyr-d-Arg-Phe-MeβAla-OH (ADAMB) was designed based on the structures of several dermorphin tetrapeptide analogues, including Nα-amidino-Tyr-d-Arg-Phe-Gly-OH (ADA-DER), H-Tyr-d-Arg-Phe-βAla-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 μ-opioid peptides. Six analogues of ADAMB were also synthesized to investigate the effect on potency of N-terminal amidination and N-methyl-β-alanine (MeβAla) 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 ED50 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 pers...