Nielsen E B, Suzdak P D, Andersen K E, Knutsen L J, Sonnewald U, Braestrup C
Laboratory of Behavioral Pharmacology, Novo Nordisk A/S, Bagsvaerd, Denmark.
Eur J Pharmacol. 1991 Apr 24;196(3):257-66. doi: 10.1016/0014-2999(91)90438-v.
Tiagabine (NO-328) (R(-)-N-[4,4-bis(3-methylthien-2-yl)but-3-enyl]nipecotic acid, hydrochloride) is a new centrally acting GABA uptake inhibitor. The anticonvulsant activity of tiagabine was evaluated against seizures induced by methyl 6,7-dimethoxy-4-ethyl-beta-carboline-3-carboxylate (DMCM), pentylenetetrazol, bicuculline, maximal electrostimulation (MES), or high intensity sound. The sedative actions of tiagabine were evaluated in tests for traction, rotarod performance and exploratory behavior. Finally, interoceptive properties of tiagabine were assessed using diazepam-, CGS 9896-, pentylenetetrazol-, or amphetamine-discriminating rats. Tiagabine was an effective anticonvulsant in doses which did not produce sedation or motor debilitation, although it was not potent against MES. In a manner similar to other anti-epileptic drugs, tiagabine potentiated dopaminergic function (methylphenidate-induced gnawing in mice) although it did not substitute for amphetamine in amphetamine-trained animals. Furthermore, although tiagabine antagonized DMCM-induced convulsions, it exhibited neither CGS 9896 or diazepam-like interoceptive effects, nor did it block (or potentiate) pentylenetetrazol-discrimination. Thus, GABA uptake inhibition represents a novel rationale for a valproate-like anticonvulsant drug therapy.
噻加宾（NO - 328）（R(-)-N-[4,4 - 双(3 - 甲基噻吩 - 2 - 基)丁 - 3 - 烯基]哌啶酸盐酸盐）是一种新型的中枢性γ-氨基丁酸（GABA）摄取抑制剂。针对由6,7 - 二甲氧基 - 4 - 乙基 - β-咔啉 - 3 - 羧酸甲酯（DMCM）、戊四氮、荷包牡丹碱、最大电刺激（MES）或高强度声音诱导的癫痫发作，对噻加宾的抗惊厥活性进行了评估。在牵引试验、转棒试验和探究行为试验中评估了噻加宾的镇静作用。最后，使用对安定、CGS 9896、戊四氮或苯丙胺有辨别能力的大鼠评估了噻加宾的内感受特性。噻加宾在不产生镇静或运动功能减退的剂量下是一种有效的抗惊厥药，尽管它对MES的作用不强。与其他抗癫痫药物类似，噻加宾增强了多巴胺能功能（甲基苯丙胺诱导的小鼠啃咬行为），尽管它在苯丙胺训练的动物中不能替代苯丙胺。此外，尽管噻加宾拮抗DMCM诱导的惊厥，但它既没有表现出CGS 9896或安定样的内感受作用，也没有阻断（或增强）戊四氮辨别。因此，GABA摄取抑制代表了一种类似丙戊酸抗惊厥药物治疗的新原理。
