RESUMO
Negative modulators of metabotropic glutamate 2 & 3 receptors demonstrate antidepressant-like activity in animal models and hold promise as novel therapeutic agents for the treatment of major depressive disorder. Herein we describe our efforts to prepare and optimize a series of conformationally constrained 3,4-disubstituted bicyclo[3.1.0]hexane glutamic acid analogs as orthosteric (glutamate site) mGlu2/3 receptor antagonists. This work led to the discovery of a highly potent and efficacious tool compound 18 (hmGlu2 IC50 46±14.2nM, hmGlu3 IC50=46.1±36.2nM). Compound 18 showed activity in the mouse forced swim test with a minimal effective dose (MED) of 1mg/kg ip. While in rat EEG studies it exhibited wake promoting effects at 3 and 10mg/kg ip without any significant effects on locomotor activity. Compound 18 thus represents a novel tool molecule for studying the impact of blocking mGlu2/3 receptors both in vitro and in vivo.
Assuntos
Antidepressivos/química , Antidepressivos/farmacologia , Transtorno Depressivo Maior/tratamento farmacológico , Ácido Glutâmico/análogos & derivados , Ácido Glutâmico/farmacologia , Receptores de Glutamato Metabotrópico/antagonistas & inibidores , Animais , Antidepressivos/farmacocinética , Compostos Bicíclicos com Pontes/química , Compostos Bicíclicos com Pontes/farmacocinética , Compostos Bicíclicos com Pontes/farmacologia , Linhagem Celular , Transtorno Depressivo Maior/metabolismo , Cães , Ácido Glutâmico/farmacocinética , Haplorrinos , Hexanos/química , Hexanos/farmacocinética , Hexanos/farmacologia , Humanos , Células Madin Darby de Rim Canino , Camundongos , Ratos , Receptores de Glutamato Metabotrópico/metabolismoRESUMO
A novel series of selective negative allosteric modulators (NAMs) for metabotropic glutamate receptor 5 (mGlu5) was discovered from an isothiazole scaffold. One compound of this series, (1R,2R)-N-(4-(6-isopropylpyridin-2-yl)-3-(2-methyl-2H-indazol-5-yl)isothiazol-5-yl)-2-methylcyclopropanecarboxamide (24), demonstrated satisfactory pharmacokinetic properties and, following oral dosing in rats, produced dose-dependent and long-lasting mGlu5 receptor occupancy. Consistent with the hypothesis that blockade of mGlu5 receptors will produce analgesic effects in mammals, compound 24 produced a dose-dependent reduction in paw licking responses in the formalin model of persistent pain.
Assuntos
Amidas/química , Amidas/farmacologia , Ciclopropanos/química , Ciclopropanos/farmacologia , Receptor de Glutamato Metabotrópico 5/metabolismo , Regulação Alostérica/efeitos dos fármacos , Amidas/farmacocinética , Animais , Comportamento Animal/efeitos dos fármacos , Ciclopropanos/farmacocinética , Ácido Glutâmico/química , Ácido Glutâmico/metabolismo , Indazóis/química , Indazóis/farmacocinética , Indazóis/farmacologia , Masculino , Ratos , Ratos Sprague-Dawley , Receptor de Glutamato Metabotrópico 5/química , Tiazóis/química , Tiazóis/farmacocinética , Tiazóis/farmacologiaRESUMO
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
A potent, selective, orally active LXR agonist was identified from focused libraries of tertiary amines. GW3965 (12) recruits the steroid receptor coactivator 1 to human LXRalpha in a cell-free ligand-sensing assay with an EC(50) of 125 nM and profiles as a full agonist on hLXRalpha and hLXRbeta in cell-based reporter gene assays with EC(50)'s of 190 and 30 nM, respectively. After oral dosing at 10 mg/kg to C57BL/6 mice, 12 increased expression of the reverse cholesterol transporter ABCA1 in the small intestine and peripheral macrophages and increased the plasma concentrations of HDL cholesterol by 30%. 12 will be a valuable chemical tool to investigate the role of LXR in the regulation of reverse cholesterol transport and lipid metabolism.