Joost H G, Habberfield A D, Simpson I A, Laurenza A, Seamon K B
Experimental Diabetes, Metabolism and Nutrition Section, MCNEB/National Institute of Arthritis, Bethesda, Maryland 20892.
Mol Pharmacol. 1988 Apr;33(4):449-53.
Forskolin and four analogues of forskolin, 7-beta-[gamma-(N'-methylpiperazino)-butyryloxy]-7-desacet ylforskolin, 7-desacetylforskolin, 7-tosyl-7-desacetylforskolin, and 1,9-dideoxyforskolin, were tested for their ability to activate adenylate cyclase, inhibit glucose transport, and inhibit cytochalasin B binding in rat adipocyte membranes. Forskolin was the most potent analogue in activating adenylate cyclase with an EC50 of 2 microM, whereas 7-beta-[gamma-(N'-methylpiperazino)butyryloxy]-7-desacety lforskolin and 7-desacetylforskolin were less potent, with EC50 values of 3 microM and 20 microM, respectively. The 7-tosyl-7-desacetylforskolin and 1,9-dideoxyforskolin did not stimulate adenylate cyclase even at the highest concentrations tested (100 microM). In contrast, forskolin and all of the analogues were able to fully inhibit glucose transport in adipocyte plasma membranes. The order of potency for the inhibition was forskolin greater than 7-beta-[gamma-(N'-methylpiperazino)butyryloxy]-7-desacety lforskolin greater than 7-desacetylforskolin greater than 7-tosyl-7-desacetylforskolin greater than 1,9-dideoxyforskolin, and the EC50 values were 0.24 microM, 1.8 microM, 7.1 microM, 8.8 microM, and 12.8 microM, respectively. Cytochalasin B binding to rat adipocyte membranes was inhibited by forskolin and the four analogues with the same order of potency as observed for the inhibition of glucose transport. Thus, the site of action of forskolin which is responsible for the inhibition of glucose transport and cytochasin B binding exhibits structural requirements for forskolin and its analogues that are different from those of the site responsible for the activation of adenylate cyclase.
对毛喉素及其四种类似物，即7-β-[γ-(N'-甲基哌嗪基)-丁酰氧基]-7-去乙酰毛喉素、7-去乙酰毛喉素、7-对甲苯磺酰基-7-去乙酰毛喉素和1,9-二脱氧毛喉素，进行了测试，以考察它们激活大鼠脂肪细胞膜中腺苷酸环化酶、抑制葡萄糖转运以及抑制细胞松弛素B结合的能力。毛喉素是激活腺苷酸环化酶最有效的类似物，其半数有效浓度（EC50）为2微摩尔，而7-β-[γ-(N'-甲基哌嗪基)丁酰氧基]-7-去乙酰毛喉素和7-去乙酰毛喉素的效力较低，EC50值分别为3微摩尔和20微摩尔。7-对甲苯磺酰基-7-去乙酰毛喉素和1,9-二脱氧毛喉素即使在测试的最高浓度（100微摩尔）下也不能刺激腺苷酸环化酶。相反，毛喉素和所有类似物都能够完全抑制脂肪细胞质膜中的葡萄糖转运。抑制效力顺序为毛喉素＞7-β-[γ-(N'-甲基哌嗪基)丁酰氧基]-7-去乙酰毛喉素＞7-去乙酰毛喉素＞7-对甲苯磺酰基-7-去乙酰毛喉素＞1,9-二脱氧毛喉素，EC50值分别为0.24微摩尔、1.8微摩尔、7.1微摩尔、8.8微摩尔和12.8微摩尔。毛喉素和这四种类似物抑制细胞松弛素B与大鼠脂肪细胞膜的结合，其效力顺序与抑制葡萄糖转运时观察到的相同。因此，毛喉素中负责抑制葡萄糖转运和细胞松弛素B结合的作用位点对毛喉素及其类似物表现出的结构要求，与负责激活腺苷酸环化酶的位点不同。
