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 D 4 receptor antagonist and serotonin reuptake inhibitor: Characterisation of its in vitro profile and pre-clinical antipsychotic potential Peter Hertel a, ⁎ , Michael Didriksen a , Bruno Pouzet a , Lise T. Brennum a , Karina K. Søby a , Anna Kirstine Larsen a , Claus T. Christoffersen a , Teresa Ramirez a , Monica M. Marcus b , Torgny H. Svensson b , Vincenzo Di Matteo c , Ennio Esposito c , Benny Bang-Andersen a , Jørn Arnt a a Research and Development, H. Lundbeck A/S, Copenhagen-Valby, Denmark b Department of Physiology and Pharmacology, The Karolinska Institutet, Sweden c Laboratory of Neurophysiology, Istituto di Ricerche Farmacologiche “Mario Negri”, Consorzio “Mario Negri” Sud, Santa Maria Imbaro (Chieti), Italy Received 7 March 2007; received in revised form 12 June 2007; accepted 18 June 2007 Available online 4 July 2007 Abstract 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 α 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. © 2007 Elsevier B.V. All rights reserved. Keywords: Antipsychotic; Dopamine D 4 receptor; 5-HT reuptake inhibition; Amphetamine; PCP 1. Introduction The antipsychotic effect of classical neuroleptic drugs such as haloperidol is generally thought to be related to antagonism of dopamine D 2 receptors in limbic structures. Although blockade of dopamine D 2 receptors is associated with effect against positive symptoms of schizophrenia, other symptoms, e.g. negative symptoms and cognitive disturbances which may be fundamental to the disease, appears less affected by conventional dopamine D 2 receptor blocking agents (Kinon and Lieberman, 1996). Further- more, as many as 25% to 60% of patients treated with conventional antipsychotics are regarded as either treatment refractory or partially responsive (Miyamoto et al., 2002). Also, the compliance with classical dopamine D 2 receptor blocking agents is clearly limited by the appearance of motor and endocrine side effects European Journal of Pharmacology 573 (2007) 148 – 160 www.elsevier.com/locate/ejphar ⁎ Corresponding author. International Clinical Research, H. Lundbeck A/S, Ottiliavej 9, DK-2500 Valby-Copenhagen, Denmark. Tel.: +45 30832518; fax: +45 36 43 82 96. E-mail address: phe@lundbeck.com (P. Hertel). 0014-2999/$ - see front matter © 2007 Elsevier B.V. All rights reserved. doi:10.1016/j.ejphar.2007.06.052