RT Journal Article
SR Electronic
T1 S33138 (<em>N</em>-[4-[2-[(3<em>aS</em>,9<em>bR</em>)-8-cyano-1,3<em>a</em>,4,9<em>b</em>-tetrahydro[1] benzopyrano[3,4-<em>c</em>]pyrrol-2(3<em>H</em>)-yl)-ethyl]phenyl-acetamide), a Preferential Dopamine D<sub>3</sub> versus D<sub>2</sub> Receptor Antagonist and Potential Antipsychotic Agent: III. Actions in Models of Therapeutic Activity and Induction of Side Effects
JF Journal of Pharmacology and Experimental Therapeutics
JO J Pharmacol Exp Ther
FD American Society for Pharmacology and Experimental Therapeutics
SP 1212
OP 1226
DO 10.1124/jpet.107.134536
VO 324
IS 3
A1 Mark J. Millan
A1 Florence Loiseau
A1 Anne Dekeyne
A1 Alain Gobert
A1 Gunnar Flik
A1 Thomas I. Cremers
A1 Jean-Michel Rivet
A1 Dorothée Sicard
A1 Rodolphe Billiras
A1 Mauricette Brocco
YR 2008
UL http://jpet.aspetjournals.org/content/324/3/1212.abstract
AB 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 D3 versus D2 receptors and does not interact with histamine H1 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 μg/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 D3 versus D2 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. The American Society for Pharmacology and Experimental Therapeutics