NAN-190: agonist and antagonist interactions with brain 5-HT1A receptors.
NAN-190: agonist and antagonist interactions with brain 5-HT1A receptors.
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NAN-190：与脑 5-HT1A 受体相互作用的激动剂和拮抗剂。
DOI：
10.1016/0006-8993(90)91759-a
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发表时间：
1990
期刊：
影响因子：
2.9
通讯作者：
Glennon,RA
中科院分区：
文献类型：
--
作者：
Rydelek-Fitzgerald,L;Teitler,M;Fletcher,PW;Ismaiel,AM;Glennon,RA
NAN-190是一种5-HT 1A拮抗剂。为了确定NAN-190的作用是否直接归因于对5-HT 1A受体的竞争性抑制，研究了5-HT 1A介导的对海马膜中腺苷酸环化酶的抑制。NAN-190（10−10-10− 5 M）本身对毛喉素刺激的腺苷酸环化酶没有影响。然而，NAN-190确实以浓度依赖性方式使5-羧酰胺色胺（5-HT 1A激动剂）对数浓度抑制曲线向右移动，这是典型的竞争性拮抗作用。Schild分析显示，使用体外腺苷酸环化酶系统的KB 5-HT 1A拮抗剂。合成了[~ 3 H]NAN-190，并对其与5-HT_（1A）受体的结合特性进行了表征，并与5-HT_（1A）激动剂放射性配体[~ 3 H]8-羟基-2-（二正丙基氨基）四氢萘（[~ 3 H]8-OH-DPAT）进行了比较。5-HT 1A受体激动剂5-HT和8-羟基-2-（二正丙胺）四氢萘（8-OH-DPAT）以相同的亲和力竞争，与用于标记5-HT 1A受体的放射性配体无关。[~ 3 H]NAN-190和[~ 3 H]8-OH-DPAT在大鼠海马、纹状体和额叶皮质中标记相同数量的位点。鸟苷-5 ′-O-（3-硫代）三磷酸（GTPγS）和5-脒基-亚氨基二磷酸（GppNHp）作为GTP的非水解类似物，抑制[~ 3 H]NAN-190的特异性结合。5′-O-（3-硫代）三磷酸腺苷（ATPγS）和5-腺苷酰亚胺二磷酸（AppNHp）无效。这种鸟苷酸特异性效应通常与激动剂放射性配体结合GTP结合蛋白偶联受体有关。[3 H]8-OH-DPAT对GTP和GTPγS的Bmax降低作用远比[3 H]NAN-190敏感。我们提出，通过不可水解的鸟苷酸减少Bmax的测试可能比用于定量激动剂活性的其他测试更敏感，并且可以证明NAN-190具有低的内在活性。总之，NAN-190在5-HT 1A受体活性的功能模型中显示出拮抗剂样性质，在放射性配体结合实验中可能显示出部分激动剂样性质。
NAN-190 has been reported to be a 5-HT1Aantagonist in drug discrimination studies. In order to determine if the effect of NAN-190 was directly due to competitive inhibition at 5-HT1Areceptors, 5-HT1A-mediated inhibition of adenylyl cyclase in hippocampal membranes was investigated. NAN-190 (10−10–10−5M), by itself, was found to have no effect on forskolin-stimulated adenylyl cyclase. NAN-190, however, did shift the 5-carboxamidotryptamine (a 5-HT1Aagonist) log-concentration inhibition curve to the right in a concentration-dependent manner, typical of competitive antagonism. Schild analysis revealed a KB 5-HT1Aantagonist using the in vitro adenylyl cyclase system. [3H]NAN-190 was synthesized and its 5-HT1Areceptor binding properties were characterized and compared with the 5-HT1Aagonist radioligand, [3H]8-hydroxy-2-(di-n-propylamino)tetralin ([3H]8-OH-DPAT). The 5-HT1Aagonists, serotonin (5-HT) and 8-hydroxy-2-(di-n-propylamine(tetralin (8-OH-DPAT) competed with equal affinities regardless of the radiogland used to label the 5-HT1Areceptors. [3H]NAN-190 and [3H]8-OH-DPAT labeled the same number of sites in rat hippocampus, striatum and frontal cortex. Guanosine-5′-O-(3-thio)triphosphate (GTPγS) and 5-guanyly;-imidodiphosphate (GppNHp)m non-hydrolyzable analogs of GTP, inhibited specific [3H]NAN-190 binding. Adenosine-5′-O-(3-thio)triphosphate (ATPγS) and 5-adenylyl-imidodiphosphate (AppNHp) were ineffective. This guanylyl nucleotide-specific effect is generally associated with agonist radioligand binding to a GTP-binding protein coupled receptor. However, [3H]8-OH-DPAT was far more sensitive than [3H]NAN-190 to the Bmaxreducing effects of GTP and GTPγS. We propose that the test for a reduction in Bmaxby non-hydrolyzable guanylyl nucleotides may be more sensitive than other tests for quantifying agonist activity and may demonstrate that NAN-190 has low intrinsic activity. In summary, NAN-190 displayed antagonist-like properties in functional models of 5-HT1Areceptor activity and possibly partial agonist-like properties in radioligand binding experiments.
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--
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