title: 2,6-Dimethyltyrosine analogues of a stereodiversified ligand library: highly potent, selective, non-peptidic mu opioid receptor agonists.
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.
authors.affiliation: Department of Chemistry and Chemical Biology, Harvard University, Cambridge, Massachusetts 02138, USA.
authors.forename: Bryce A
authors.initials: BA
authors.lastname: Harrison
authors.forename: Gavril W
authors.initials: GW
authors.lastname: Pasternak
authors.forename: Gregory L
authors.initials: GL
authors.lastname: Verdine
mesh_terms: D000818:Animals; D001667:Binding, Competitive; D002460:Cell Line; D002531:Cerebellum / Q000378:metabolism; D006224:Cricetinae; D006168:Guinea Pigs; D006801:Humans; D066298:In Vitro Techniques; D008024:Ligands; D011869:Radioligand Assay; D017450:Receptors, Opioid, mu / Q000819:agonists* / Q000378:metabolism; D013237:Stereoisomerism; D013329:Structure-Activity Relationship; D014443:Tyrosine / Q000031:analogs & derivatives* / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology
chemical_list: D008024:Ligands; D017450:Receptors, Opioid, mu; C076121:2',6'-dimethyltyrosine; D014443:Tyrosine