RESUMO
Drugs that selectively activate estrogen receptor ß (ERß) are potentially safer than the nonselective estrogens currently used in hormonal replacement treatments that activate both ERß and ERα. The selective ERß agonist AC-186 was evaluated in a rat model of Parkinson's disease induced through bilateral 6-hydroxydopamine lesions of the substantia nigra. In this model, AC-186 prevented motor, cognitive, and sensorimotor gating deficits and mitigated the loss of dopamine neurons in the substantia nigra, in males, but not in females. Furthermore, in male rats, 17ß-estradiol, which activates ERß and ERα with equal potency, did not show the same neuroprotective benefits as AC-186. Hence, in addition to a beneficial safety profile for use in both males and females, a selective ERß agonist has a differentiated pharmacological profile compared to 17ß-estradiol in males.
Assuntos
Cicloexanos/uso terapêutico , Receptor beta de Estrogênio/agonistas , Fármacos Neuroprotetores/uso terapêutico , Transtornos Parkinsonianos/tratamento farmacológico , Fenóis/uso terapêutico , Animais , Corpo Estriado/química , Corpo Estriado/efeitos dos fármacos , Corpo Estriado/patologia , Cicloexanos/química , Cicloexanos/farmacologia , Citocinas/análise , Avaliação Pré-Clínica de Medicamentos , Estradiol/uso terapêutico , Comportamento Exploratório/efeitos dos fármacos , Feminino , Masculino , Estrutura Molecular , Proteínas do Tecido Nervoso/análise , Fármacos Neuroprotetores/química , Fármacos Neuroprotetores/farmacologia , Ovariectomia , Oxidopamina/toxicidade , Transtornos Parkinsonianos/induzido quimicamente , Fenóis/química , Fenóis/farmacologia , Ratos , Ratos Sprague-Dawley , Reflexo de Sobressalto/efeitos dos fármacos , Teste de Desempenho do Rota-Rod , Fatores Sexuais , Substância Negra/química , Substância Negra/efeitos dos fármacos , Substância Negra/patologia , Tirosina 3-Mono-Oxigenase/análiseRESUMO
1-(Benzothiazol-2-yl)-1-(4-chlorophenyl)ethanol (1) was identified as a positive allosteric modulator (PAM) of the CaSR in a functional cell-based assay. This compound belongs to a class of compounds that is structurally distinct from other known positive allosteric modulators, for example, the phenylalkylamines cinacalcet, a modified analog (13) potently suppressed parathyroid hormone (PTH) release in rats, consistent with its profile as a PAM of CaSRs.