Hertel Peter, Didriksen Michael, Pouzet Bruno, Brennum Lise T, Søby Karina K, Larsen Anna Kirstine, Christoffersen Claus T, Ramirez Teresa, Marcus Monica M, Svensson Torgny H, Di Matteo Vincenzo, Esposito Ennio, Bang-Andersen Benny, Arnt Jørn
Research and Development, H. Lundbeck A/S, Copenhagen-Valby, Denmark.
Eur J Pharmacol. 2007 Nov 14;573(1-3):148-60. doi: 10.1016/j.ejphar.2007.06.052. Epub 2007 Jul 4.
The present study describes the pharmacological profile of the putative antipsychotic drug Lu 35-138 ((+)-(S)-3-{1-[2-(1-acetyl-2,3-dihydro-1H-indol-3-yl)ethyl]-3,6-dihydro-2H-pyridin-4-yl}-6-chloro-1H-indole). The in vitro receptor profile of Lu 35-138 revealed high affinity (K(i)=5 nM) and competitive antagonism (K(b)=8 nM) at dopamine D(4) receptors combined with potent 5-HT uptake inhibition (IC(50)=3.2 nM) and moderate alpha(1)-adrenoceptor affinity (K(i)=45 nM). In vivo, Lu 35-138 selectively counteracted hyperlocomotion induced by d-amphetamine (0.5 mg/kg; ED(50)=4.0 mg/kg, s.c.) in rats and phencyclidine (PCP; 2.5 mg/kg; ED(50)=13 mg/kg, s.c.) in mice. Lu 35-138 was unable to affect hyperlocomotion induced by a high dose of d-amphetamine (2.0 mg/kg), which indicates a preferential action on limbic versus striatal structures. A similar limbic selectivity of Lu 35-138 was indicated in voltammetric measure of dopamine output in the core and shell subdivisions of the nucleus accumbens in rats. Furthermore, a relatively large dose of Lu 35-138 (18 mg/kg, s.c.) counteracted d-amphetamine-induced disruption of pre-pulse inhibition in rats and repeated administration of Lu 35-138 (0.31 or 1.25 mg/kg, p.o. once daily for 3 weeks) reduced the number of spontaneously active dopamine neurones in the ventral tegmental area, underlining its antipsychotic-like profile. Lu 35-138 failed to induce catalepsy in rats or dystonia in Cebus apella monkeys and did not deteriorate spatial memory in rats as assessed by water maze performance. Collectively, these results suggest that Lu 35-138 possesses antipsychotic activity combined with a low extrapyramidal and cognitive side effect liability.
本研究描述了假定的抗精神病药物Lu 35 - 138（(+)-(S)-3-{1-[2-(1-乙酰基-2,3-二氢-1H-吲哚-3-基)乙基]-3,6-二氢-2H-吡啶-4-基}-6-氯-1H-吲哚）的药理学特性。Lu 35 - 138的体外受体特性显示，它对多巴胺D(4)受体具有高亲和力（K(i)=5 nM）和竞争性拮抗作用（K(b)=8 nM），同时具有强效的5-羟色胺摄取抑制作用（IC(50)=3.2 nM）和中等程度的α(1)-肾上腺素能受体亲和力（K(i)=45 nM）。在体内，Lu 35 - 138能选择性地对抗由d-苯丙胺（0.5 mg/kg；ED(50)=4.0 mg/kg，皮下注射）诱导的大鼠运动亢进以及由苯环己哌啶（PCP；2.5 mg/kg；ED(50)=13 mg/kg，皮下注射）诱导的小鼠运动亢进。Lu 35 - 138无法影响高剂量d-苯丙胺（2.0 mg/kg）诱导的运动亢进，这表明它对边缘系统与纹状体结构具有优先作用。在对大鼠伏隔核核心和壳部多巴胺输出的伏安法测量中，也显示出Lu 35 - 138具有类似的边缘系统选择性。此外，相对大剂量的Lu 35 - 138（18 mg/kg，皮下注射）能对抗d-苯丙胺诱导的大鼠前脉冲抑制破坏，并且重复给予Lu 35 - 138（0.31或1.25 mg/kg，口服，每日一次，持续3周）可减少腹侧被盖区自发活动的多巴胺神经元数量，突出了其抗精神病样特性。Lu 35 - 138未能在大鼠中诱导僵住症或在僧帽猴中诱导肌张力障碍，并且通过水迷宫实验评估，它也未使大鼠的空间记忆恶化。总体而言，这些结果表明Lu 35 - 138具有抗精神病活性，同时锥体外系和认知副作用风险较低。
