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.