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

• 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
• ISSN: 0027-8424; 1091-6490
• DOI: 10.1073/pnas.90.22.10811

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).