RESUMO
The discovery of the CNS-penetrant and selective alpha(2C) adrenergic receptor antagonist N-{2-[4-(2,3-dihydro-benzo[1,4]dioxin-2-ylmethyl)-[1,4]diazepan-1-yl]-ethyl}-2-phenoxy-nicotinamide, 13 is described. Structure-activity studies demonstrate the structural requirements for binding affinity, functional activity, and selectivity over other alpha(2)-AR subtypes.
Assuntos
Antagonistas de Receptores Adrenérgicos alfa 2 , Azepinas/síntese química , Niacinamida/análogos & derivados , Niacinamida/síntese química , Animais , Azepinas/farmacologia , Encéfalo/metabolismo , Sistema Nervoso Central/efeitos dos fármacos , Líquido Cefalorraquidiano/metabolismo , Química Farmacêutica/métodos , Desenho de Fármacos , Humanos , Cinética , Masculino , Conformação Molecular , Niacinamida/farmacologia , Ratos , Ratos Endogâmicos WKY , Receptores Adrenérgicos alfa 2/química , Relação Estrutura-AtividadeRESUMO
A cell-based assay for the chemokine G-protein-coupled receptor CCR4 was developed, and used to screen a small-molecule compound collection in a multiplex format. A series of bipiperidinyl carboxylic acid amides amenable to parallel chemistry were derived that were potent and selective antagonists of CCR4. One prototype compound was shown to be active in a functional model of chemotaxis, making it a useful chemical tool to explore the role of CCR4 in asthma, allergy, diabetes, and cancer.
Assuntos
Amidas/química , Amidas/farmacologia , Biperideno/química , Ácidos Carboxílicos/química , Receptores de Quimiocinas/antagonistas & inibidores , Concentração Inibidora 50 , Estrutura Molecular , Receptores CCR4 , Receptores de Quimiocinas/metabolismo , Estereoisomerismo , Relação Estrutura-AtividadeRESUMO
An early drug discovery approach focusing on gene families can benefit from strategies that exploit common signaling mechanisms to more effectively identify and characterize novel chemical lead structures. Multiplexing, defined as the screening of multiple targets within the same experiment, is an example of this strategy. Here, the authors describe a technique that allows multiplexing of a common assay type used to study G-protein-coupled receptors: changes in intracellular Ca2+ levels as measured by Molecular Device's fluorometric imaging plate reader (FLIPR). The multiplexed FLIPR assays showed the expected pharmacological properties of single assays, with good reproducibility and Z* factors. The authors used them to screen large compound libraries in 2 multiplexed assay designs. The 1st used a single-cell line expressing 2 different receptors and the 2nd a mixture of 2 cell lines of the same type each expressing distinct receptors. Screening using these multiplexed assays produced significant savings in reagents, time, and human resources and allowed the authors to quickly identify specific and selective hits.
