2,6-Dimethyltyrosine Analogues of a Stereodiversified Ligand Library: Highly Potent, Selective, Non-Peptidic μ Opioid Receptor Agonists
- 29 January 2003
- journal article
- Published by American Chemical Society (ACS) in Journal of Medicinal Chemistry
- Vol. 46 (5) , 677-680
- https://doi.org/10.1021/jm025608s
Abstract
We recently reported the use of an exhaustively stereodiversified library based on endomorphin-2 (1) to discover μ opioid receptor (MOR) ligands of type 2−4. Here, we report the synthesis and evaluation of 2,6-dimethyltyrosine analogues 5−10. These analogues showed improved affinity for MOR relative to 2−4. In the cases of 5 and 6, we synthesized and evaluated five stereoisomers of each, thereby discovering stereoisomers with unexpected potency, selectivity, and efficacy. These results illustrate the utility of acyclic, stereodiverse libraries.Keywords
This publication has 18 references indexed in Scilit:
- High-Affinity Mu Opioid Receptor Ligands Discovered by the Screening of an Exhaustively Stereodiversified Library of 1,5-EnediolsJournal of the American Chemical Society, 2002
- Use of Biomimetic Diversity-Oriented Synthesis to Discover Galanthamine-Like Molecules with Biological Properties beyond Those of the Natural ProductJournal of the American Chemical Society, 2001
- New Approaches to Olefin Cross-MetathesisJournal of the American Chemical Society, 1999
- Endomorphins: Novel Endogenous μ‐Opiate Receptor Agonists in Regions of High μ‐Opiate Receptor DensityAnnals of the New York Academy of Sciences, 1999
- Further Studies on the Dmt-Tic Pharmacophore: Hydrophobic Substituents at the C-Terminus Endow δ Antagonists To Manifest μ Agonism or μ AntagonismJournal of Medicinal Chemistry, 1999
- A potent and selective endogenous agonist for the µ-opiate receptorNature, 1997
- Enkephalin Analogs as Systemically Active Antinociceptive Agents: O- and N-Alkylated Derivatives of the Dipeptide Amide L-2,6-Dimethyltyrosyl-N-(3-phenylpropyl)-D-alaninamideJournal of Medicinal Chemistry, 1994
- Systemic analgesic activity and .delta.-opioid selectivity in [2,6-dimethyl-Tyr1, D-Pen2, D-Pen5]enkephalinJournal of Medicinal Chemistry, 1992
- .beta.-Proline analogs as agonists at the strychnine-sensitive glycine receptorJournal of Medicinal Chemistry, 1992
- Simple and convenient synthesis of tert-butyl ethers of Fmoc-serine, Fmoc-threonine, and Fmoc-tyrosineThe Journal of Organic Chemistry, 1991