新型异吲哚啉衍生物DN - 2327与大脑中GABAB受体的关联及激动作用

Association and agonistic action of DN-2327, a novel isoindoline derivative, GABAB receptor in brain.

作者信息

Ichida T, Hirouchi M, Mizutani H, Narihara R, Kuriyama K

机构信息

Department of Pharmacology, Kyoto Prefectural University of Medicine, Japan.

出版信息

Eur J Pharmacol. 1994 Mar 15;267(1):43-7. doi: 10.1016/0922-4106(94)90222-4.

DOI:10.1016/0922-4106(94)90222-4

PMID:7911433

Abstract

The association and action of DN-2327, 2-(7-chloro-1,8-naphthyridin-2-yl)-3-[(1,4-dioxa-8- azaspiro[4,5]dec-8-yl)carbonylmethyl]isoindolin-1-one, on the gamma-aminobutyric acid (GABA)B receptor in rat brain have been examined. DN-2327 inhibited the binding of [3H]GABA to GABAB receptor in crude synaptic membrane obtained from rat brain. The Scatchard analysis of [3H]GABA binding to GABAB receptor indicated that DN-2327 induced the decrease in affinity of both high and low affinity binding sites without changing the Bmax values. The forskolin-stimulated adenylate cyclase activity in slices from rat cerebral cortex was significantly suppressed by the addition of DN-2327. Furthermore, this inhibition by DN-2327 was eliminated by the simultaneous additions of 2-hydroxy saclofen or CGP 55845A, GABAB receptor antagonists. These results suggest that DN-2327 may have not only a high association with GABAB receptor but also an agonistic action on the receptor.

摘要

已对2-(7-氯-1,8-萘啶-2-基)-3-[(1,4-二氧杂-8-氮杂螺[4,5]癸-8-基)羰基甲基]异吲哚啉-1-酮（DN-2327）在大鼠脑中γ-氨基丁酸（GABA）B受体上的结合及作用进行了研究。DN-2327抑制了从大鼠脑获得的粗制突触膜中[3H]GABA与GABAB受体的结合。对[3H]GABA与GABAB受体结合的Scatchard分析表明，DN-2327导致高亲和力和低亲和力结合位点的亲和力降低，而Bmax值不变。添加DN-2327可显著抑制大鼠大脑皮层切片中福斯高林刺激的腺苷酸环化酶活性。此外，同时添加GABAB受体拮抗剂2-羟基舒氯芬或CGP 55845A可消除DN-2327的这种抑制作用。这些结果表明，DN-2327不仅可能与GABAB受体有高度亲和力，而且对该受体有激动作用。