Carruba M, Tomello C, Briscini L, Nisoli E
Centre for the Study and Research on Obesity, LITA Vialba, School of Medicine, Ospedale L. Sacco, University of Milan, Italy.
Int J Obes Relat Metab Disord. 1998 Aug;22 Suppl 1:S13-6; discussion S17.
Anorectic drugs are increasingly being used in obesity to induce and/or maintain weight loss. We have focused on the development of metabolic enhancers. These compounds increase energy expenditure, which is important because weight loss is associated with metabolic re-adjustment to reduce energy output. Thus, metabolic enhancers ensure that energy expenditure is maintained when food intake is reduced. Beta3-adrenoceptor agonists are thermogenic agents that increase energy output by stimulating heat generation. Early selective beta3-agonists were effective in producing weight loss in obese rats, but were largely ineffective in humans. In addition, many interacted with other types of beta receptor to produce side-effects. The development of a Chinese hamster ovary cell (CHO) transfection system, using the human beta3-adrenoceptor gene, resulted in potential new selective human beta3-agonists being identified. However, the in vitro activity of these agents does not necessarily reflect their action in vivo, due to the presence of other receptor types and G proteins in the target cells, and interactions between them. The characterization of a selective beta3-antagonist, SR59230A, has allowed us to examine beta3-agonist activity in different experimental systems. The CHO transfection system has been used to show that SR59230A is effective in blocking agonist activity against both the rat adrenoceptor, and three human beta3-receptor isoforms. In addition, SR59230A shows competitive inhibition of agonist activity in both rat and human model systems. This antagonist may therefore provide a pharmacological tool for the functional study of by newly identified beta3-receptor agonists.
食欲抑制剂越来越多地被用于肥胖治疗以诱导和/或维持体重减轻。我们专注于代谢增强剂的研发。这些化合物可增加能量消耗，这很重要，因为体重减轻与代谢重新调整以降低能量输出有关。因此，代谢增强剂可确保在减少食物摄入时维持能量消耗。β3肾上腺素能受体激动剂是产热剂，通过刺激产热来增加能量输出。早期的选择性β3激动剂在肥胖大鼠中能有效减轻体重，但在人类中大多无效。此外，许多这类激动剂会与其他类型的β受体相互作用而产生副作用。利用人β3肾上腺素能受体基因开发的中国仓鼠卵巢细胞（CHO）转染系统，使得潜在的新型选择性人β3激动剂得以被识别。然而，由于靶细胞中存在其他受体类型和G蛋白以及它们之间的相互作用，这些药物的体外活性不一定能反映其体内作用。选择性β3拮抗剂SR59230A的特性使我们能够在不同实验系统中检测β3激动剂活性。CHO转染系统已被用于证明SR59230A能有效阻断针对大鼠肾上腺素能受体以及三种人β3受体亚型的激动剂活性。此外，SR59230A在大鼠和人类模型系统中均表现出对激动剂活性的竞争性抑制。因此，这种拮抗剂可能为新发现的β3受体激动剂的功能研究提供一种药理学工具。
