Truncation of the peptide sequence in bifunctional ligands with mu and delta opioid receptor agonist and neurokinin 1 receptor antagonist activities

• Published in: Bioorganic & medicinal chemistry letters 2013-09, Vol.23 (17), p.4975-4978
• Main Authors: Nair, Padma, Yamamoto, Takashi, Largent-Milnes, Tally M., Cowell, Scott, Kulkarni, Vinod, Moye, Sharif, Navratilova, Edita, Davis, Peg, Ma, Shou-Wu, Vanderah, Todd W., Lai, Josephine, Porreca, Frank, Hruby, Victor J.
• Format: Article
• Language: English
• Subjects: agonists; Amino Acid Sequence; amino acid sequences; Analgesics - chemistry; Analgesics - pharmacology; Analgesics - therapeutic use; Animals; antagonists; Bifunctional compounds; Humans; Ligands; Neurokinin-1 Receptor Antagonists - chemistry; Neurokinin-1 Receptor Antagonists - pharmacology; Neurokinin-1 Receptor Antagonists - therapeutic use; Neutokinin-1 receptor antagonists; NMR structure; Opioid receptor agonists; Peptides - chemistry; Peptides - pharmacology; Peptides - therapeutic use; Rats; Receptors, Neurokinin-1 - metabolism; Receptors, Opioid, delta - agonists; Receptors, Opioid, delta - metabolism; Receptors, Opioid, mu - agonists; Receptors, Opioid, mu - metabolism; substance P; Truncation of peptide sequence
• ISSN: 0960-894X; 1464-3405
• DOI: 10.1016/j.bmcl.2013.06.065

The optimization and truncation of our lead peptide-derived ligand TY005 possessing eight amino-acid residues was performed. Among the synthesized derivatives, NP30 (Tyr1-DAla2-Gly3-Phe4-Gly5-Trp6-O-[3′,5′-Bzl(CF3)2]) showed balanced and potent opioid agonist as well as substance P antagonist activities in isolated tissue-based assays, together with significant antinociceptive and antiallodynic activities in vivo.