2,6-Dimethyltyrosine analogues of a stereodiversified ligand library: highly potent, selective, non-peptidic mu opioid receptor agonists

Bryce A Harrison; Gavril W Pasternak; Gregory L Verdine

doi:10.1021/jm025608s

2,6-Dimethyltyrosine analogues of a stereodiversified ligand library: highly potent, selective, non-peptidic mu opioid receptor agonists

J Med Chem. 2003 Feb 27;46(5):677-80. doi: 10.1021/jm025608s.

Authors

Bryce A Harrison¹, Gavril W Pasternak, Gregory L Verdine

Affiliation

¹ Department of Chemistry and Chemical Biology, Harvard University, Cambridge, Massachusetts 02138, USA.

PMID: 12593647
DOI: 10.1021/jm025608s

Abstract

We recently reported the use of an exhaustively stereodiversified library based on endomorphin-2 (1) to discover mu 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.

Publication types

Research Support, Non-U.S. Gov't
Research Support, U.S. Gov't, Non-P.H.S.
Research Support, U.S. Gov't, P.H.S.

MeSH terms

Animals
Binding, Competitive
Cell Line
Cerebellum / metabolism
Cricetinae
Guinea Pigs
Humans
In Vitro Techniques
Ligands
Radioligand Assay
Receptors, Opioid, mu / agonists*
Receptors, Opioid, mu / metabolism
Stereoisomerism
Structure-Activity Relationship
Tyrosine / analogs & derivatives*
Tyrosine / chemical synthesis*
Tyrosine / chemistry
Tyrosine / pharmacology

Substances

Ligands
Receptors, Opioid, mu
2',6'-dimethyltyrosine
Tyrosine