AN ALL D-AMINO-ACID OPIOID PEPTIDE WITH CENTRAL ANALGESIC ACTIVITY FROM A COMBINATORIAL LIBRARY

A synthetic combinatorial library containing 52,128,400 D-amino acid h exapeptides was used to identify a ligand for the mu opioid receptor. The peptide, Ac-rfwink-NH2, bears no resemblance to any known opioid p eptide. Simulations using molecular dynamics, however, showed that thr ee amino acid moieties have the same spatial orientation as the corres ponding pharmacophoric groups of the opioid peptide PLO17. Ac-rfwink-N H2 was shown to be a potent agonist at the mu receptor and induced lon g-lasting analgesia in mice. Analgesia produced by intraperitoneally a dministered Ac-rfwink-NH2 was blocked by intracerebroventricular admin istration of naloxone, demonstrating that this peptide may cross the b lood-brain barrier.