Standifer K M, Pitha J, Baker S P
Department of Pharmacology, University of Florida, College of Medicine, Gainesville 32610.
Naunyn Schmiedebergs Arch Pharmacol. 1989 Jan-Feb;339(1-2):129-37. doi: 10.1007/BF00165134.
The interaction of the carbostyril derivatives 5-[2-[[1-(4-aminophenyl)-2-methyl-prop-2-yl]amino]-1-hydroxyethyl]- 8-hydroxycarbostyril (carbo-amine) and 5-[2-[[3-[4-(bromoacetamido)phenyl]-2-methylprop-2-yl]amino]-1- hydroxyethyl]-8-hydroxycarbostyril (carbo-Br) with the rat reticulocyte beta-adrenoreceptor system has been partially characterized. In the absence of a guanine nucleotide, the concentration of carbo-amine, carbo-Br and (-)isoprenaline that inhibited (-)-[125I]iodocyanopindolol ([125I]CYP) binding by 50% (IC50) was 5.9 +/- 0.2, 3.3 +/- 0.3 and 49 +/- 3 nM, respectively. In the presence of a guanine nucleotide, the IC50 values were carbo-amine, 21 +/- 0.6 nM; carbo-Br, 7.6 +/- 0.3 nM and (-)isoprenaline, 813 +/- 66 nM. Preincubation of membranes with either of the carbostyril congeners followed by washing reduced specific [125I]CYP binding capacity without changing the KD value for the remaining receptors. The beta-antagonist nadolol largely prevented the receptor reduction induced by the carbostyril compounds. Incubation of membranes for 18 h at 25 degrees C resulted in an 11% recovery of the carbo-amine-induced receptor loss and no recovery of the receptors lost by preincubation with carbo-Br. However, the carbo-amine induced receptor loss could be largely reversed (80%) by membrane heating at 45 degrees C whereas little reversal (less than 10%) was observed with the carbo-Br pretreated membranes. The concentration of carbo-amine, carbo-Br and (-)isoprenaline that stimulated half-maximal cAMP formation in reticulocyte membranes was 17.8 +/- 3.1, 8.2 +/- 2.1 and 241 +/- 17 nM, respectively, and all 3 agonists produced the same maximal response. Initial cAMP formation stimulated by the carbostyril derivatives and (-)isoprenaline was blocked by concurrent addition of propranolol after 7 min of incubation with either of the two carbostyril derivatives did not affect further cAMP production whereas with (-)isoprenaline further cAMP production was blocked.(ABSTRACT TRUNCATED AT 250 WORDS)
已对咔唑醇衍生物5-[2-[[1-(4-氨基苯基)-2-甲基-丙-2-基]氨基]-1-羟乙基]-8-羟基咔唑醇（咔唑醇胺）和5-[2-[[3-[4-(溴乙酰胺基)苯基]-2-甲基丙-2-基]氨基]-1-羟乙基]-8-羟基咔唑醇（咔唑醇-Br）与大鼠网织红细胞β-肾上腺素受体系统的相互作用进行了部分表征。在不存在鸟嘌呤核苷酸的情况下，抑制（-）-[125I]碘氰吲哚洛尔（[125I]CYP）结合50%（IC50）的咔唑醇胺、咔唑醇-Br和（-）异丙肾上腺素的浓度分别为5.9±0.2、3.3±0.3和49±3 nM。在存在鸟嘌呤核苷酸的情况下，IC50值分别为：咔唑醇胺，21±0.6 nM；咔唑醇-Br，7.6±0.3 nM；（-）异丙肾上腺素，813±66 nM。用任一种咔唑醇同系物预孵育膜后洗涤，可降低特异性[125I]CYP结合能力，而不改变剩余受体的KD值。β-拮抗剂纳多洛尔在很大程度上可防止咔唑醇化合物诱导的受体减少。在25℃下将膜孵育18小时，咔唑醇胺诱导的受体损失有11%恢复，而用咔唑醇-Br预孵育导致的受体损失未恢复。然而，咔唑醇胺诱导的受体损失在45℃下加热膜时可在很大程度上逆转（80%），而用咔唑醇-Br预处理的膜几乎没有逆转（不到10%）。在网织红细胞膜中刺激半数最大cAMP形成的咔唑醇胺、咔唑醇-Br和（-）异丙肾上腺素的浓度分别为17.8±3.1、8.2±2.1和241±17 nM，并且所有3种激动剂产生相同的最大反应。在与两种咔唑醇衍生物之一孵育7分钟后同时加入普萘洛尔可阻断咔唑醇衍生物和（-）异丙肾上腺素刺激的初始cAMP形成，而用咔唑醇衍生物之一孵育不影响进一步的cAMP产生，而用（-）异丙肾上腺素则进一步的cAMP产生被阻断。（摘要截短于250字）
