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), a dopamine D₄ receptor antagonist and serotonin reuptake inhibitor: C

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• 作者：Peter Hertel ; Michael Didriksen ; Bruno Pouzet ; Lise T. Brennum ; Karina K. Sø ; by ; Anna Kirstine Larsen ; Claus T. Christoffersen ; Teresa Ramirez ; Monica M. Marcus ; Torgny H. Svensson ; Vincenzo Di Ma
• 关键词：Antipsychotic ; Dopamine D₄ receptor ; 5-HT reuptake inhibition ; Amphetamine ; PCP
• 刊名：European Journal of Pharmacology
• 出版年：2007
• 出版时间：14 November 2007
• 年：2007
• 卷：573
• 期：1-3
• 页码：148-160
• 全文大小：436 K

文摘

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 D₄ receptors combined with potent 5-HT uptake inhibition (IC₅₀ = 3.2 nM) and moderate α₁-adrenoceptor affinity (K_i = 45 nM). In vivo, Lu 35-138 selectively counteracted hyperlocomotion induced by mCaps"">d-amphetamine (0.5 mg/kg; ED₅₀ = 4.0 mg/kg, s.c.) in rats and phencyclidine (PCP; 2.5 mg/kg; ED₅₀ = 13 mg/kg, s.c.) in mice. Lu 35-138 was unable to affect hyperlocomotion induced by a high dose of mCaps"">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 mCaps"">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.