Acetalins: Opioid Receptor Antagonists Determined Through the use of Synthetic Peptide Combinatorial Libraries

A synthetic peptide combinatorial library made up of 52,128,400 hexapeptides, each having an acetyl group at the N terminus and an amide group on the C terminus, was screened to find compounds able to displace tritiated [D-Ala2, MePhe4, Gly-ol5]enkephalin from μ opioid receptor binding sites in crud...

Full description

Saved in:
Bibliographic Details
Published in:Proceedings of the National Academy of Sciences - PNAS 1993-11, Vol.90 (22), p.10811-10815
Main Authors: Dooley, C. T., Chung, N. N., Schiller, P. W., Houghten, R. A.
Format: Article
Language:English
Subjects:
Amides
Amino Acid Sequence
Amino acids
Animals
Biochemistry
Biological and medical sciences
Brain - metabolism
Enkephalin, Ala-MePhe-Gly
Enkephalins - metabolism
Guinea Pigs
Ileum
In Vitro Techniques
Inhibitory concentration 50
Libraries
Ligands
Medical sciences
Molecular Sequence Data
Neuropharmacology
Neurotransmitters. Neurotransmission. Receptors
Oligopeptides - chemical synthesis
Oligopeptides - metabolism
Opioid analgesics
Opioid receptors
Pain
Peptidergic system (neuropeptide, opioid peptide, opiates...). Adenosinergic and purinergic systems
Pharmacology. Drug treatments
Rats
Receptors
Receptors, Opioid, mu - antagonists & inhibitors
Citations: Items that cite this one
Online Access:Get full text
Tags: Add Tag
No Tags, Be the first to tag this record!
Description
Summary:A synthetic peptide combinatorial library made up of 52,128,400 hexapeptides, each having an acetyl group at the N terminus and an amide group on the C terminus, was screened to find compounds able to displace tritiated [D-Ala2, MePhe4, Gly-ol5]enkephalin from μ opioid receptor binding sites in crude rat brain homogenates. Individual peptides with μ receptor affinity were found using an iterative process for successively determining the most active peptide mixtures. Upon completion of this iterative process, the three peptides with the highest affinity were Ac-RFMWMT-NH2, Ac-RFMWMR-NH2, and Ac-RFMWMK-NH2. These peptides showed high affinity for μ and κ3opioid receptors, somewhat lower affinity for δ receptors, weak affinity for κ1receptors, and no affinity for κ2receptors. They were found to be potent μ receptor antagonists in the guinea pig ileum assay and relatively weak antagonists in the mouse vas deferens assay. These peptides represent a class of opioid receptor ligands that we have termed acetalins (acetyl plus enkephalin).
ISSN:0027-8424
1091-6490
DOI:10.1073/pnas.90.22.10811