RESUMO
The melanocortin 4 receptor (MC4R) plays an important role in body weight regulation and energy homeostasis. Administration of peptidic MC4R antagonists (usually by intracerebro ventricular injection) has been shown in the literature to increase body weight and/or food intake in several rodent models. We report here the identification of a novel nonpeptidic MC4R antagonist and its effects on tumor-induced weight loss in mice following peripheral administration.
Assuntos
Benzamidinas/síntese química , Emaciação/tratamento farmacológico , Imidazóis/síntese química , Neoplasias/complicações , Receptor Tipo 4 de Melanocortina/antagonistas & inibidores , Administração Cutânea , Animais , Benzamidinas/química , Benzamidinas/farmacologia , Emaciação/etiologia , Imidazóis/química , Imidazóis/farmacologia , Camundongos , Camundongos Endogâmicos BALB C , Transplante de Neoplasias , Ensaio Radioligante , Relação Estrutura-Atividade , Transplante HeterólogoRESUMO
The identification and optimization of a series of acylguanidine-based melanocortin-4 receptor antagonists is discussed.
Assuntos
Guanidina/química , Receptor Tipo 4 de Melanocortina/antagonistas & inibidores , Compostos de Sulfidrila/química , Animais , Sítios de Ligação , Encéfalo/metabolismo , Guanidina/análogos & derivados , Guanidina/farmacologia , Concentração Inibidora 50 , Camundongos , Plasma/metabolismo , Relação Estrutura-Atividade , Compostos de Sulfidrila/farmacologia , Fatores de TempoRESUMO
Chemokine-induced T lymphocyte recruitment to the lung is critical for allergic inflammation, but chemokine signaling pathways are incompletely understood. Regulator of G protein signaling (RGS)16, a GTPase accelerator (GTPase-activating protein) for Galpha subunits, attenuates signaling by chemokine receptors in T lymphocytes, suggesting a role in the regulation of lymphocyte trafficking. To explore the role of RGS16 in T lymphocyte-dependent immune responses in a whole-organism model, we generated transgenic (Tg) mice expressing RGS16 in CD4(+) and CD8(+) cells. rgs16 Tg T lymphocytes migrated to CC chemokine ligand 21 or CC chemokine ligand 12 injection sites in the peritoneum, but not to CXC chemokine ligand 12. In a Th2-dependent model of allergic pulmonary inflammation, CD4(+) lymphocytes bearing CCR3, CCR5, and CXCR4 trafficked in reduced numbers to the lung after acute inhalation challenge with allergen (OVA). In contrast, spleens of sensitized and challenged Tg mice contained increased numbers of CD4(+)CCR3(+) cells producing more Th2-type cytokines (IL-4, IL-5, and IL-13), which were associated with increased airway hyperreactivity. Migration of Tg lymphocytes to the lung parenchyma after adoptive transfer was significantly reduced compared with wild-type lymphocytes. Naive lymphocytes displayed normal CCR3 and CXCR4 expression and cytokine responses, and compartmentation in secondary lymphoid organs was normal without allergen challenge. These results suggest that RGS16 may regulate T lymphocyte activation in response to inflammatory stimuli and migration induced by CXCR4, CCR3, and CCR5, but not CCR2 or CCR7.
Assuntos
Quimiotaxia de Leucócito/imunologia , Inflamação/imunologia , Pulmão/patologia , Ativação Linfocitária/imunologia , Proteínas/fisiologia , Proteínas RGS/fisiologia , Transdução de Sinais/imunologia , Subpopulações de Linfócitos T/imunologia , Subpopulações de Linfócitos T/patologia , Doença Aguda , Transferência Adotiva , Alérgenos/administração & dosagem , Animais , Diferenciação Celular/genética , Diferenciação Celular/imunologia , Células Cultivadas , Quimiotaxia de Leucócito/genética , Cruzamentos Genéticos , Citocinas/biossíntese , Citocinas/metabolismo , Feminino , Homeostase/genética , Homeostase/imunologia , Humanos , Imunização , Inflamação/genética , Inflamação/patologia , Pulmão/imunologia , Ativação Linfocitária/genética , Tecido Linfoide/crescimento & desenvolvimento , Tecido Linfoide/imunologia , Masculino , Camundongos , Camundongos Endogâmicos BALB C , Camundongos Transgênicos , Ovalbumina/administração & dosagem , Ovalbumina/imunologia , Biossíntese de Proteínas , Proteínas/genética , Proteínas RGS/biossíntese , Proteínas RGS/genética , Receptores de Quimiocinas/antagonistas & inibidores , Receptores de Quimiocinas/fisiologia , Transdução de Sinais/genética , Subpopulações de Linfócitos T/metabolismo , Subpopulações de Linfócitos T/transplante , Regulação para Cima/genética , Regulação para Cima/imunologiaRESUMO
A novel series of imidazole-based small molecule antagonists of the melanocortin 4 receptor (MC4-R) is reported. Members of this series have been identified, which exhibit sub-micromolar binding affinity for the MC4-R, functional potency <100nM, and good oral exposure in rat. Antagonists of the MC4-R are potentially useful in the therapeutic treatment of involuntary weight loss due to advanced age or disease (e.g. cancer or AIDS), an area of large, unmet medical need.