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 hexapeptides was used to identify a ligand for the mu opioid receptor. The peptide, Ac-rfwink-NH2, bears no resemblance to any known opioid peptide. Simulations using molecular dynamics, however, showed that three amino acid moieties have the same spatial orientation as the corresponding pharmacophoric groups of the opioid peptide PLO17. Ac-rfwink-NH2 was shown to be a potent agonist at the mu receptor and induced long-lasting analgesia in mice. Analgesia produced by intraperitoneally administered Ac-rfwink-NH2 was blocked by intracerebroventricular administration of naloxone, demonstrating that this peptide may cross the blood-brain barrier.
Dooley
C T
CT
Torrey Pines Institute for Molecular Studies, San Diego, CA 92121.
Chung
N N
NN
Wilkes
B C
BC
Schiller
P W
PW
Bidlack
J M
JM
Pasternak
G W
GW
Houghten
R A
RA
D000595:Amino Acid Sequence; D000700:Analgesics / Q000737:chemistry / Q000378:metabolism / Q000494:pharmacology*; D000818:Animals; D001921:Brain / Q000378:metabolism; D004305:Dose-Response Relationship, Drug; D004723:Endorphins / Q000494:pharmacology; D020875:Enkephalin, Ala(2)-MePhe(4)-Gly(5)-; D020881:Enkephalin, D-Penicillamine (2,5)-; D004745:Enkephalins / Q000378:metabolism; D006168:Guinea Pigs; D007276:Injections, Intraventricular; D008297:Male; D051379:Mice; D008958:Models, Molecular; D008969:Molecular Sequence Data; D009270:Naloxone / Q000008:administration & dosage / Q000494:pharmacology; D018847:Opioid Peptides / Q000737:chemistry / Q000378:metabolism / Q000494:pharmacology*; D010147:Pain Measurement; D011487:Protein Conformation; D051381:Rats; D017450:Receptors, Opioid, mu / Q000819:agonists / Q000378:metabolism; D013237:Stereoisomerism
D000700:Analgesics; D004723:Endorphins; D004745:Enkephalins; D018847:Opioid Peptides; D017450:Receptors, Opioid, mu; C091134:acetyl-arginyl-phenylalanyl-tryptophyl-isoleucyl-asparaginyl-lysine; D020875:Enkephalin, Ala(2)-MePhe(4)-Gly(5)-; D009270:Naloxone; C044708:morphiceptin, N-Me-Phe(3)-; D020881:Enkephalin, D-Penicillamine (2,5)-