In contrast to clinically available
antipsychotics, the novel benzopyranopyrrolidine derivative,
S33138 (N-[4-[2-[(3aS,9bR)-8-cyano-1,3a,4,9b-tetrahydro[1]benzopyrano[3,4-c]pyrrol-2(3H)-yl)-ethyl]phenyl-
acetamide), behaves as a preferential antagonist of D(3) versus D(2) receptors and does not interact with
histamine H(1) and
muscarinic receptors. In contrast to
haloperidol,
clozapine,
olanzapine, and
risperidone,
S33138 (0.16-2.5 mg/kg s.c.) did not disrupt performance in passive-avoidance and five-choice serial reaction time procedures. Furthermore, upon either systemic administration (0.04-2.5 mg/kg s.c.) or introduction into the frontal cortex (0.04-0.63 mug/side),
S33138 potently attenuated the perturbation of social recognition by
scopolamine or a prolonged intersession delay. Over a comparable and low-dose range,
S33138 (0.04-0.63 mg/kg s.c.) elevated dialysis levels of
acetylcholine in the frontal cortex of freely moving rats. At higher doses (2.5-10.0 mg/kg s.c.),
S33138 also increased frontocortical levels of
histamine, whereas monoamines,
glutamate,
glycine, and
GABA were unaffected. By analogy to the other
antipsychotics,
S33138 (0.63-10.0 mg/kg s.c.) inhibited conditioned avoidance responses in rats,
apomorphine-induced climbing in mice, and hyperlocomotion elicited by
amphetamine,
cocaine,
dizocilpine,
ketamine, and
phencyclidine in rats.
S33138 (0.16-2.5 mg/kg s.c.) also blocked the reduction of prepulse inhibition elicited by
apomorphine. In comparison with the above actions, only "high" doses of
S33138 (10.0-40.0 mg/kg s.c.) elicited
catalepsy. To summarize, reflecting preferential blockade of D(3) versus D(2) receptors,
S33138 preserves and/or enhances cognitive function, increases frontocortical
cholinergic transmission, and is active in models of
antipsychotic properties at doses well below those inducing
catalepsy. In comparison with clinically available agents,
S33138 displays, thus, a distinctive and promising profile of potential
antipsychotic properties.