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
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Research Support, Non-U.S. Gov't
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Research Support, U.S. Gov't, Non-P.H.S.
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Research Support, U.S. Gov't, P.H.S.
MeSH terms
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Animals
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Binding, Competitive
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Cell Line
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Cerebellum / metabolism
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Cricetinae
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Guinea Pigs
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Humans
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In Vitro Techniques
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Ligands
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Radioligand Assay
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Receptors, Opioid, mu / agonists*
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Receptors, Opioid, mu / metabolism
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Stereoisomerism
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Structure-Activity Relationship
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Tyrosine / analogs & derivatives*
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Tyrosine / chemical synthesis*
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Tyrosine / chemistry
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Tyrosine / pharmacology
Substances
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Ligands
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Receptors, Opioid, mu
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2',6'-dimethyltyrosine
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Tyrosine