RESUMO
Thyroid hormone receptors (TRs) are nuclear receptors that are activated by thyroid hormone ligands and co-regulator proteins. Two receptor subtypes, TRalpha and TRbeta, have been suggested to play a role in numerous physiological functions. However, specificity of receptor subtype function and co-regulator interaction is unclear due to the lack of TR subtype-specific ligands. Five TR ligands were evaluated for their selectivity and interaction with the TR subtypes. A multiplex assay was used to identify co-regulator peptide interaction, and biochemical assays were used to characterize ligand-receptor specificity. In the biochemical assay, rank order ligand potencies were similar in the presence of co-activator peptides, SRC1-2 and SRC3-2, and the co-repressor peptide, NCoR1-2, with T3 and Triac potencies greater in the presence of the co-repressor. The potency of Tetrac was similar regardless of the co-regulator used while T4 and rT3 demonstrated selectivity for TRalpha subtype. The rank order among TR ligands at either receptor subtype in the biochemical assay correlated with the multiplex assay. These assays can be used to identify new ligands that can provide further insight into TR biology.
Assuntos
Receptores dos Hormônios Tireóideos/metabolismo , Sequência de Aminoácidos , Animais , Bioensaio , Bovinos , Ligantes , Dados de Sequência Molecular , Proteínas Nucleares/metabolismo , Correpressor 1 de Receptor Nuclear , Peptídeos/química , Peptídeos/metabolismo , Ligação Proteica , Proteínas Repressoras/metabolismo , Especificidade por SubstratoRESUMO
The discovery of a series of 4-aminoethyl-3-(phenylsulfonyl)-1H-indoles, dual acting norepinephrine reuptake inhibitors (NRIs) and 5-HT(2A) receptor antagonists, is described. The synthesis and structure-activity relationship (SAR) of this novel series of compounds is also presented.
Assuntos
Indóis/farmacologia , Inibidores da Captação de Neurotransmissores/síntese química , Inibidores da Captação de Neurotransmissores/farmacologia , Norepinefrina/metabolismo , Antagonistas do Receptor 5-HT2 de Serotonina , Antagonistas da Serotonina/síntese química , Antagonistas da Serotonina/farmacologia , Transporte Biológico/efeitos dos fármacos , Linhagem Celular , Humanos , Indóis/síntese química , Indóis/metabolismo , Inibidores da Captação de Neurotransmissores/metabolismo , Receptor 5-HT2A de Serotonina/metabolismo , Antagonistas da Serotonina/metabolismo , Relação Estrutura-AtividadeRESUMO
A series of novel 1- or 3-(3-amino-1-phenyl propyl)-1,3-dihydro-2H-benzimidazol-2-ones as selective norepinephrine reuptake inhibitors was discovered. Several compounds such as 15 and 20 showed good hNET potency. Compounds 15 and 20 also displayed excellent selectivity at hNET that appeared superior to those of reboxetine and atomoxetine (4 and 5).
Assuntos
Benzimidazóis/síntese química , Benzimidazóis/farmacologia , Inibidores da Captação de Neurotransmissores/síntese química , Inibidores da Captação de Neurotransmissores/farmacologia , Norepinefrina/antagonistas & inibidores , Benzimidazóis/química , Técnicas de Química Combinatória , Desenho de Fármacos , Humanos , Estrutura Molecular , Inibidores da Captação de Neurotransmissores/química , Norepinefrina/metabolismo , EstereoisomerismoRESUMO
Norepinephrine and serotonin play an important role in a wide variety of biological processes and are implicated in a number of neurological disorders. A novel class of 1-(3-amino-1-phenylpropyl)indolin-2-ones was designed and synthesized that displays potent norepinephrine reuptake inhibition while maintaining high selectivity (>100-fold) against the human serotonin and dopamine transporters.
Assuntos
Indóis/síntese química , Indóis/farmacologia , Inibidores da Captação de Neurotransmissores/síntese química , Inibidores da Captação de Neurotransmissores/farmacologia , Norepinefrina/antagonistas & inibidores , Humanos , Indóis/química , Estrutura Molecular , Inibidores da Captação de Neurotransmissores/química , Estereoisomerismo , Relação Estrutura-AtividadeRESUMO
Extensive efforts are under way to identify antiangiogenic therapies for the treatment of human cancers. Many proposed therapeutics target vascular endothelial growth factor (VEGF) or the kinase insert domain receptor (KDR/VEGF receptor-2/FLK-1), the mitogenic VEGF receptor tyrosine kinase expressed by endothelial cells. Inhibition of KDR catalytic activity blocks tumor neoangiogenesis, reduces vascular permeability, and, in animal models, inhibits tumor growth and metastasis. Using a gene expression profiling strategy in rat tumor models, we identified a set of six genes that are selectively overexpressed in tumor endothelial cells relative to tumor cells and whose pattern of expression correlates with the rate of tumor endothelial cell proliferation. In addition to being potential targets for antiangiogenesis tumor therapy, the expression patterns of these genes or their protein products may aid the development of pharmacodynamic assays for small molecule inhibitors of the KDR kinase in human tumors.
Assuntos
Biomarcadores Tumorais , Perfilação da Expressão Gênica/métodos , Inibidores da Angiogênese/farmacologia , Animais , Linhagem Celular Tumoral , Proliferação de Células , Primers do DNA/química , Células Endoteliais/citologia , Endotélio Vascular/citologia , Humanos , Imuno-Histoquímica , Microcirculação/citologia , Microscopia de Fluorescência , Metástase Neoplásica , Transplante de Neoplasias , Neovascularização Patológica , Análise de Sequência com Séries de Oligonucleotídeos , Ratos , Ratos Endogâmicos F344 , Reação em Cadeia da Polimerase Via Transcriptase Reversa , Fatores de Tempo , Fator A de Crescimento do Endotélio Vascular/metabolismo , Receptor 2 de Fatores de Crescimento do Endotélio Vascular/metabolismoRESUMO
Efforts to identify new selective and potent norepinephrine reuptake inhibitors (NRIs) for multiple indications by structural modification of the previous 3-(arylamino)-3-phenylpropan-2-olamine scaffold led to the discovery of a novel series of 1-(indolin-1-yl)-1-phenyl-3-propan-2-olamines (9). Investigation of the structure-activity relationships revealed that small alkyl substitution at the C3 position of the indoline ring enhanced selectivity for the norepinephrine transporter (NET) over the serotonin transporter (SERT). Several compounds bearing a 3,3-dimethyl group on the indoline ring, 9k, 9o,p, and 9s,t, exhibited potent inhibition of NET (IC(50) = 2.7-6.5 nM) and excellent selectivity over both serotonin and dopamine transporters. The best example from this series, 9p, a potent and highly selective NRI, displayed oral efficacy in a telemetric rat model of ovariectomized-induced thermoregulatory dysfunction, a mouse p-phenylquinone (PPQ) model of acute visceral pain, and a rat spinal nerve ligation (SNL) model of neuropathic pain.
Assuntos
Indóis/farmacologia , Inibidores da Captação de Neurotransmissores/química , Inibidores da Captação de Neurotransmissores/farmacologia , Proteínas da Membrana Plasmática de Transporte de Norepinefrina/antagonistas & inibidores , Propanolaminas/farmacologia , Animais , Regulação da Temperatura Corporal/efeitos dos fármacos , Feminino , Indóis/síntese química , Indóis/química , Espectroscopia de Ressonância Magnética , Inibidores da Captação de Neurotransmissores/síntese química , Proteínas da Membrana Plasmática de Transporte de Norepinefrina/metabolismo , Dor/tratamento farmacológico , Propanolaminas/síntese química , Propanolaminas/química , Ratos , Espectrometria de Massas por Ionização por Electrospray , Relação Estrutura-AtividadeRESUMO
Sequential structural modifications of the aryloxypropanamine template (e.g., atomoxetine, 2) led to a novel series of 1-(3-amino-2-hydroxy-1-phenyl propyl)-1,3-dihydro-2H-benzimidazol-2-ones as selective norepinephrine reuptake inhibitors (NRIs). In general, this series of compounds potently blocked the human norepinephrine transporter (hNET) while exhibiting selectivity at hNET against both the human serotonin (hSERT) and dopamine transporters (hDAT). Numerous compounds (e.g., 19-22) had low nonamolar hNET potency with IC(50) values of 7-10 nM and excellent selectivity (>500 fold) at hNET over hSERT and hDAT. Several compounds, such as 20 and 22, were tested in a telemetric rat model of ovariectomized-induced thermoregulatory dysfunction and were efficacious at oral doses of 3 mg/kg in reducing the tail skin temperature. In addition, compound 20 was also studied in the rat hot plate and spinal nerve ligation (SNL) models of acute and neuropathic pain, respectively, and was orally efficacious at doses of 3-10 mg/kg.
Assuntos
Benzimidazóis/química , Benzimidazóis/farmacologia , Inibidores da Captação de Neurotransmissores/química , Inibidores da Captação de Neurotransmissores/farmacologia , Norepinefrina/metabolismo , Administração Oral , Animais , Comportamento Animal/efeitos dos fármacos , Benzimidazóis/administração & dosagem , Benzimidazóis/farmacocinética , Transporte Biológico/efeitos dos fármacos , Proteínas da Membrana Plasmática de Transporte de Dopamina/antagonistas & inibidores , Feminino , Humanos , Hiperalgesia/fisiopatologia , Masculino , Inibidores da Captação de Neurotransmissores/administração & dosagem , Inibidores da Captação de Neurotransmissores/farmacocinética , Proteínas da Membrana Plasmática de Transporte de Norepinefrina/antagonistas & inibidores , Propanolaminas/química , Ratos , Ratos Sprague-Dawley , Proteínas da Membrana Plasmática de Transporte de Serotonina/metabolismo , Nervos Espinhais/efeitos dos fármacos , Nervos Espinhais/fisiologia , Relação Estrutura-Atividade , Especificidade por SubstratoRESUMO
Further exploration of the cycloalkanol ethylamine scaffold, of which venlafaxine ( 1) is a member, was undertaken to develop novel and selective norepinephrine reuptake inhibitors (NRIs) for evaluation in a variety of predictive animal models. These efforts led to the discovery of a piperazine-containing analogue, 17g (WY-46824), that exhibited potent norepinephrine reuptake inhibition, excellent selectivity over the serotonin transporter, but no selectivity over the dopamine transporter. Synthesis and testing of a series of cyclohexanol ethylpiperazines identified ( S)-(-)- 17i (WAY-256805), a potent norepinephrine reuptake inhibitor (IC 50 = 82 nM, K i = 50 nM) that exhibited excellent selectivity over both the serotonin and dopamine transporters and was efficacious in animal models of depression, pain, and thermoregulatory dysfunction.