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: characterisation of its in vitro profile and pre-clinical antipsychotic potential.
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.
Hertel
Peter
P
Research and Development, H. Lundbeck A/S, Copenhagen-Valby, Denmark. phe@lundbeck.com
Didriksen
Michael
M
Pouzet
Bruno
B
Brennum
Lise T
LT
Søby
Karina K
KK
Larsen
Anna Kirstine
AK
Christoffersen
Claus T
CT
Ramirez
Teresa
T
Marcus
Monica M
MM
Svensson
Torgny H
TH
Di Matteo
Vincenzo
V
Esposito
Ennio
E
Bang-Andersen
Benny
B
Arnt
Jørn
J
D058668:Adrenergic alpha-1 Receptor Antagonists; D000818:Animals; D021461:Animals, Outbred Strains; D001569:Benzodiazepines / Q000494:pharmacology; D002428:Cebus; D015283:Citalopram / Q000494:pharmacology; D003024:Clozapine / Q000494:pharmacology; D003071:Cognition / Q000187:drug effects; D004095:Dihydropyridines / Q000737:chemistry / Q000494:pharmacology*; D004305:Dose-Response Relationship, Drug; D004353:Drug Evaluation, Preclinical / Q000379:methods; D005260:Female; D006220:Haloperidol / Q000494:pharmacology; D000882:Haplorhini; D006801:Humans; D007211:Indoles / Q000737:chemistry / Q000494:pharmacology*; D008297:Male; D051379:Mice; D015394:Molecular Structure; D009043:Motor Activity / Q000187:drug effects*; D000077152:Olanzapine; D010879:Piperazines / Q000737:chemistry / Q000494:pharmacology; D051381:Rats; D017207:Rats, Sprague-Dawley; D017208:Rats, Wistar; D050638:Receptors, Dopamine D4 / Q000037:antagonists & inhibitors*; D018967:Risperidone / Q000494:pharmacology; D017367:Selective Serotonin Reuptake Inhibitors / Q000737:chemistry / Q000494:pharmacology*; D013449:Sulfonamides / Q000494:pharmacology; D000096926:Benzenesulfonamides
D058668:Adrenergic alpha-1 Receptor Antagonists; D001569:Benzodiazepines; D015283:Citalopram; D003024:Clozapine; D004095:Dihydropyridines; D006220:Haloperidol; D007211:Indoles; D000077152:Olanzapine; D010879:Piperazines; D050638:Receptors, Dopamine D4; D018967:Risperidone; D017367:Selective Serotonin Reuptake Inhibitors; D013449:Sulfonamides; C527164:3-(1-(2-(1-acetyl-2,3-dihydro-1H-indol-3-yl)ethyl)-3,6-dihydro-2H-pyridin-4-yl)-6-chloro-1H-indole; C527165:5-(4-(4-chlorophenyl)piperazin-1-ylmethyl)-1H-indole; C100448:sonepiprazole; D000096926:Benzenesulfonamides