LABELING OF PERIPHERAL-TYPE BENZODIAZEPINE BINDING-SITES IN THE RAT-BRAIN BY USING [PK-H-3 11195, AN ISOQUINOLINE CARBOXAMIDE DERIVATIVE - KINETIC-STUDIES AND AUTORADIOGRAPHIC LOCALIZATION
LABELING OF PERIPHERAL-TYPE BENZODIAZEPINE BINDING-SITES IN THE RAT-BRAIN BY USING [PK-H-3 11195, AN ISOQUINOLINE CARBOXAMIDE DERIVATIVE - KINETIC-STUDIES AND AUTORADIOGRAPHIC LOCALIZATION
复制标题
DOI：
10.1111/j.1471-4159.1983.tb00888.x
复制
发表时间：
1983-01-01
影响因子：
4.7
通讯作者：
LEFUR, G
中科院分区：
文献类型：
--
作者：
BENAVIDES, J;QUARTERONET, D;LEFUR, G
PK 11195 [1-（2-氯苯基）-N-甲基-N-（1-甲基丙基）-3-异喹啉甲酰胺]是外周型苯二氮卓类药物结合位点的新配体，与苯二氮卓类药物化学性质无关。它以非常高的效力（IC 50. 10-9 M）[3 H]-RO 5 -4864 [对氯苯基地西泮]（一种专门标记外周型位点的苯二氮卓类药物）从其结合位点。[3 H]PK 11195以可饱和和可逆的方式与大鼠大脑皮层和大鼠嗅球的膜部分结合，亲和力非常高（Kd = 10-9 M）。最大结合位点的数量是十倍以上的嗅球比大脑皮层。几种化合物在25 ℃下作为置换剂的效力顺序。C（PK 11195 > RO 5 -4864 >地西泮>双嘧达莫>氯硝西泮）表明[3 H]PK 11195与外周型苯二氮卓类结合位点结合。[3 H]PK 11195结合的Kd值不受温度变化的影响，而RO 5 -4864和地西泮亲和力随温度升高而降低。[~ 3 H]PK 11195与大鼠脑切片结合的放射自显影图像显示，结合位点主要位于嗅球、正中隆起、脉络丛和室管膜。这种配体可能是一个有用的工具，以阐明这些结合位点的生理和药理学相关性。
PK 11195 [1-(2-chlorophenyl)-N-methyl-N-(1-methylpropyl)-3-isoquinolinecarboxamide] is a new ligand for the peripheral-type benzodiazepine binding sites, chemically unrelated to benzodiazepines. It displaces with a very high potency (IC50 .simeq. 10-9 M) [3H]-RO5-4864 [p-chlorophenyl diazepam] (a benzodiazepine which specifically labels the peripheral-type sites) from its binding sites. [3H]PK 11195 binds to a membrane fraction from rat brain cortex and rat olfactory bulb in a saturable and reversible manner with a very high affinity (Kd = 10-9 M). The number of maximal binding sites was ten times greater in the olfactory bulb than in the brain cortex. The order of potency of several compounds as displacers at 25.degree. C (PK 11195 > RO5-4864 > diazepam > dipyridamole > clonazepam) demonstrates that [3H]PK 11195 binds to the peripheral-type benzodiazepine binding sites. The Kd value for the [3H]PK 11195 binding is not affected by temperature changes, whereas RO5-4864 and diazepam affinities decrease with increasing temperatures. Autoradiographic images of [3H]PK 11195 binding to rat brain sections show that binding sites are mainly localized in the olfactory bulb, median eminence, choroid plexus and ependyma. This ligand could be a useful tool to elucidate the physiological and pharmacological relevance of these binding sites.