326 to be useful in predicting the clinical response of novel antipsychotic candidates. (Portions of this work were supported by Bristol-Myers Squibb and Wyeth-Ayerst Laboratories.) Pharmacological evaluation of sertindole: zyxwvutsrqponmlkjihgfedcbaZYXWVUTSRQPONMLKJ A new atypical neuroleptic T. Skarsfeldt zyxwvutsrqponmlkjihgfedcbaZYXWVUTSRQPONMLKJIHGFEDCBA Phannocolo@ al Research, H. Lundbcck AIS, Ottiliovej 9, 2500 Copenhagen, Valby, Denmark In addition to the antipsychotic activity, the classical neuroleptics (e.g. haloperidol) induce extrapyramidal side effects (EPS). The EPS are believed to be a consequence of an inhibition of the nigrostriatal dopamine (DA) system. Inhibition of the mesolimbic DA system is believed to be involved in the antipsychotic potential of a compound. The first atypical antipsychotic compound which did not induce EPS in man, clozapine, preferentially inhibits the mesolimbic DA activity in animal studies. Within a series of substituted indoles we have recently identified a new potential neuroleptic compound, sertindole, which has a remarkable pharmacological profile and which possesses a high selectivity for limbic areas. In vitro, sertindole has high affinity for central .5-HT2, DA D-2 and alpha-l-receptors with less or no affinity for other receptors. In vivo sertindole shows very potent and long lasting 5-HK! receptor blockade (i.e. antagonism of LSD cue and quipazine-induced head twitches) while having no acute antagonistic activity on the DA system (i.e. induces no catalepsy and does not inhibit methylphenidate-or amphetamine-induced behavioural activity). After repeated administration (21 days) sertindole dose-dependently decreases the number of active DA neurones in ventral tegmental area (AlO) (ED50 = 0.010 micromol/kg/day). Much higher doses are needed to inhibit the spontaneously active DA neurones in substantia nigra pars compacta (A9) (ED50 = 1.6 micro- mol/kg/day). Acute electrophysiological experiments suggest that, incontrast to both clozapine and haloperidol, sertindole is without direct activity on the DA neurones in A9 and A10 areas. This pharmacological profile suggests that sertindole is a potential antipsychotic compound which should induce fewer extrapyramidal side-effects than classical neuroleptics. Effect of typical and atypical antipsychotic drugs on the in vivo binding of [3H] N-methyl-spiperone to serotonin-2 and dopamine-2 receptors in rat brain C.A. Stockmeier*, S. Matsubara, Y. Zhang, H.Y. Meltzer Department of Psychiatv, Case W eslem Reserve University School of Medicine, Hanna Pavilion, Room B-68, 2040 Abington Road, Cleveland, OH 44106, U.S.A. Antipsychotic drugs (APD) have been classified based on their ability to displace in vitro binding of radioligands to serotonin-2 (SHT-2) receptors in the frontal cortex and dopamine-2 (DA-2) receptors in the striatum of rats (JPET 254:238, 1989). Atypical APD have lower affinity for DA-2 binding sites than typical APD, while both atypical and typical APD have similar affinities for 5HT-2 binding sites. Consequently, atypical APD have higher ratios than typical APD of the pKi values for 5HT-2 binding divided by the pKi values for DA-2 binding. We sought to determine if this in vitro distinction between atypical and typical APD could also be obtained in vivo. Invivo binding of [3H]n-methyl-spiperone ([3H]NMSP) to SHT-2 receptors in frontal cortex and DA-2 receptors in striatum and olfactory tubercle was performed according to the technique of Frost et al, 1987. In vivo drug competition studies with ritanserin, cinanserin and raclopride indicated that [3H]NMSP selectively labeled 5HT-2 binding sites in frontal cortex and DA-2 binding sites in striatum and olfactory tubercle. The atypical APD amperozide, fluperlapine, clozapine and melperone were less potent in vivo than the typical APD chlorpromazine, haloperidol, fluphenazine and loxapine in displacing DA-2 receptor binding in striatum and olfactory tubercle. However, tiospirone, the atypical APD with the highest affinity for the .5HT-2 receptor in vivo and in vitro, was much more potent than the other atypical APD in displacing DA-2 receptor binding. Thioridazine, a typical APD, was similar to the atypical APD in having low potency for the DA-2