RESUMO
As part of our ongoing efforts to identify novel ligands for the metabotropic glutamate 2 and 3 (mGlu2/3) receptors, we have incorporated substitution at the C3 and C4 positions of the (1S,2R,5R,6R)-2-amino-bicyclo[3.1.0]hexane-2,6-dicarboxylic acid scaffold to generate mGlu2/3 antagonists. Exploration of this structure-activity relationship (SAR) led to the identification of (1S,2R,3S,4S,5R,6R)-2-amino-3-[(3,4-difluorophenyl)sulfanylmethyl]-4-hydroxy-bicyclo[3.1.0]hexane-2,6-dicarboxylic acid hydrochloride (LY3020371·HCl, 19f), a potent, selective, and maximally efficacious mGlu2/3 antagonist. Further characterization of compound 19f binding to the human metabotropic 2 glutamate (hmGlu2) site was established by cocrystallization of this molecule with the amino terminal domain (ATD) of the hmGlu2 receptor protein. The resulting cocrystal structure revealed the specific ligand-protein interactions, which likely explain the high affinity of 19f for this site and support its functional mGlu2 antagonist pharmacology. Further characterization of 19f in vivo demonstrated an antidepressant-like signature in the mouse forced-swim test (mFST) assay when brain levels of this compound exceeded the cellular mGlu2 IC50 value.
Assuntos
Antidepressivos/farmacologia , Comportamento Animal/efeitos dos fármacos , Descoberta de Drogas , Receptores de Glutamato Metabotrópico/antagonistas & inibidores , Animais , Antidepressivos/síntese química , Antidepressivos/química , Encéfalo/efeitos dos fármacos , Cicloexanos/síntese química , Cicloexanos/química , Cicloexanos/farmacologia , Relação Dose-Resposta a Droga , Humanos , Masculino , Camundongos , Camundongos Endogâmicos , Modelos Moleculares , Estrutura Molecular , Atividade Motora/efeitos dos fármacos , Receptores de Glutamato Metabotrópico/química , Receptores de Glutamato Metabotrópico/isolamento & purificação , Relação Estrutura-Atividade , NataçãoRESUMO
Synchrotron X-ray sources provide the highest quality crystallographic data for structure-guided drug design. In general, industrial utilization of such sources has been intermittent and occasionally limited. The Lilly Research Laboratories Collaborative Access Team (LRL-CAT) beamline provides a unique alternative to traditional synchrotron use by pharmaceutical and biotechnology companies. Crystallographic experiments at LRL-CAT and the results therefrom are integrated directly into the drug discovery process, permitting structural data, including screening of fragment libraries, to be routinely and rapidly used on a daily basis as part of pharmaceutical lead discovery and optimization. Here we describe how LRL-CAT acquires and disseminates the results from protein crystallography to maximize their impact on the development of new potential medicines.
