RESUMO
Many tribal populations are characterized by health disparities, including higher rates of infection, metabolic syndrome, and cancer-all of which are mediated by the immune system. Members of the Navajo Nation have suffered chronic low-level exposure to metal mixtures from uranium mine wastes for decades. We suspect that such metal and metalloid exposures lead to adverse health effects via their modulation of immune system function. We examined the relationships between nine key metal and metalloid exposures (in blood and urine) with 11 circulating biomarkers (cytokines and CRP in serum) in 231 pregnant Navajo women participating in the Navajo Birth Cohort Study. Biomonitored levels of uranium and arsenic species were considerably higher in participants than NHANES averages. Each biomarker was associated with a unique set of exposures, and arsenic species were generally immunosuppressive (decreased cellular and humoral stimulating cytokines). Overall, our results suggest that environmental metal and metalloid exposures modulate immune status in pregnant Navajo women, which may impact long-term health outcomes in mothers and their children.
Assuntos
Arsênio , Indígenas Norte-Americanos , Urânio , Gravidez , Criança , Humanos , Feminino , Estudos de Coortes , Urânio/análise , Arsênio/efeitos adversos , Citocinas , Inquéritos Nutricionais , Coorte de Nascimento , BiomarcadoresRESUMO
Adamantanyl benzamide 1 was identified as a potent P2X7R antagonist but failed to progress further due to poor metabolic stability. We describe the synthesis and SAR of a series of bioisosteres of benzamide 1 to explore improvements in the pharmacological properties of this lead. Initial efforts investigated a series of heteroaromatic bioisosteres, which demonstrated improved physicochemical properties but reduced P2X7R antagonism. Installation of bioisosteric fluorine on the adamantane bridgeheads was well tolerated and led to a series of bioisosteres with improved physicochemical properties and metabolic stability. Trifluorinated benzamide 34 demonstrated optimal physicochemical parameters, superior metabolic stability (ten times longer than lead benzamide 1), and an improved physicokinetic profile and proved effective in the presence of several known P2X7R polymorphisms.
Assuntos
Adamantano/análogos & derivados , Benzamidas/farmacologia , Antagonistas do Receptor Purinérgico P2X/farmacologia , Receptores Purinérgicos P2X7/efeitos dos fármacos , Adamantano/farmacologia , Animais , Benzamidas/síntese química , Benzamidas/química , Benzamidas/farmacocinética , Biotransformação , Avaliação Pré-Clínica de Medicamentos , Estabilidade de Medicamentos , Humanos , Microssomos Hepáticos/metabolismo , Estrutura Molecular , Oxirredução , Polimorfismo de Nucleotídeo Único , Antagonistas do Receptor Purinérgico P2X/síntese química , Antagonistas do Receptor Purinérgico P2X/química , Antagonistas do Receptor Purinérgico P2X/farmacocinética , Ratos , Receptores Purinérgicos P2X7/genética , Relação Estrutura-AtividadeRESUMO
The pharmacological actions of 2,6-di-tert-butyl-4-(3-hydroxy-2-spiropentylpropyl)-phenol (BSPP), a putative presynaptic GABA(B) receptor modulator, were examined in electrically stimulated rat neocortical brain slices preloaded with [3H]-GABA or [3H]-glutamic acid. At 10 mmol/L, BSPP inhibited the release of [3H]-GABA in the presence of baclofen, but not that of [3H]-glutamic acid. This effect was sensitive to the GABA(B) receptor antagonist (+)-(S)-5,5-dimethylmorpholinyl-2-acetic acid (Sch 50911). Alone, BSPP had no effect on the release of [3H]-GABA or [3H]-glutamic acid. It is concluded that BSPP selectively potentiates the action of baclofen at GABA(B) autoreceptors, but not heteroreceptors and may be a useful ligand to discriminate between presynaptic GABA(B) receptor subtypes.