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Science 23 December 1994:
Vol. 266. no. 5193, pp. 2019 - 2022
DOI: 10.1126/science.7801131
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Articles

Science, Vol 266, Issue 5193, 2019-2022
Copyright © 1994 by American Association for the Advancement of Science

articles

An all D-amino acid opioid peptide with central analgesic activity from a combinatorial library

CT Dooley, NN Chung, BC Wilkes, PW Schiller, JM Bidlack, GW Pasternak, and RA Houghten

Torrey Pines Institute for Molecular Studies, San Diego, CA 92121.

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.


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