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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
326 to be useful in predicting the clinical response of novel antipsychotic supported by Bristol-Myers Squibb and Wyeth-Ayerst Laboratories.)
Pharmacological
evaluation
of sertindole:
candidates.
(Portions
of this work were
A new atypical neuroleptic
T. Skarsfeldt 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 micromol/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 Weslem 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
327
binding site in vivo. Both typical and atypical APD displaced 5HT-2 binding in vivo in cortex with similar affinities. There were significant positive correlations between the ability of the APD to displace DA-2 receptor binding in vitro and in vivo, and to displace 5HT-2 receptor binding in vitro and in vivo. The typical APD loxapine was more potent in vivo than in vitro in competing for 5HT-2 or DA-2 binding sites. These results indicate that the ratio of potency of APD in displacing DA-2 and 5HT-2 receptor binding both in vivo and in vitro discriminates between typical and atypical APD. The atypical APD may achieve their antischizophrenic action without blocking DA-2 receptors in vivo.
Phase I trials of BMY 14802, a potential antipsychotic sigma binding sites
with affinity for
D.P. Taylor*‘, U.A. Shukla2, S.A. Wolfe, Jr.4, P.Q. Owen3, R. Pyke3, E.B. DeSouza4 ‘CNS Drug Discovery, ‘Metabolism and Pharmacokinetics, and 3CNS Clinical Development, Bristol-Meyers Squibb Pharmaceutical Research Institute, Wallingforrl, CT 06492-7660, U.S.A., and 4AaUiction Research Center, National Institate on DragAbuse, Baltimore, MD 21224, U.S.A.
BMY 14802 has emerged as a potential antipsychotic with a preclinical profile consistent with efficacy comparable to available antipsychotics and with greater apparent safety. It is active in traditional models of antipsychotic efficacy as well as newer models such as the attenuation of behaviors elicited by chronic amphetamine intoxication in monkeys. Its potential for safety in long-term use is suggested by its lack of effect on D-2 dopamine receptors or neuronal activity in the substantia nigra after chronic administration to rats. BMY 14802 exhibits selective affinity for the limbic system in its effects on dopamine and its metabolites, but it does not bind to D-2 or D-l dopamine receptors in vitro or in vivo. BMY 14802 exhibits potent, steroselective competitive inhibition of binding to u sites. The R( + ) enantiomer is more potent at the u site and the 5-HTlA receptor than the S(-) enantiomer. Phase I trials of BMY 14802 have been completed. The first single dose study was carried out in 109 healthy male volunteers. Oral doses ranging from 2 to 800 mg were administered with 6 subjects in each dose group except 4 at 700 and 2 at 800 mg. A safety endpoint was reached at the 800 mg dose. A second 28 day multiple dose, double-blind, placebo-controlled safety, tolerance, and pharmacokinetic study was carried out in 22 healthy volunteers. Oral doses of 200,300,400 and 500 mg were administered on a q.i.d. schedule. The drug was well tolerated with no reportable side effects. In particular, no signs of movement disorders were observed. Subjects receiving BMY 14802 had elevated levels of u binding on peripheral blood leucocytes compared to subjects receiving placebo. Leucocyte binding was not correlated with Cm, or AUC values for blood levels of BMY 14802. If BMY 14802 were au “antagonist”, it might be expected that long-term administration of the drug would result in u “supersensitivity.” In fact, Bremer et al. (Sot. Neurosci. Abst. 15: 1216, 1989) have observed this phenomenon with BMY 14802 in the rat. Should future well-controlled clinical trials demonstrate clinical efficacy, BMY 14802 may act by a novel mechanism to treat the symptoms of schizophrenia with reduced liability for the side effects (extrapyramidal side effects, cardiotoxicity, agranulocytosis) of currently-available drugs.
Initial experience with clozapine in Oregon’s State Hospitals W.H. Wilson Department of Psychiatry, Oregon Health Sciences Universily, 3181 S. W. Sam Jackson Park Road, OPO2, Portlanti, OR 97201-3098, USA.
Controlled clinical trials and compassionate use protocols have indicated that clozapine is of significant therapeutic benefit to many individuals with otherwise treatment-resistant schizophrenia, at least when used in these carefully controlled circumstances. Clozapine therapy has been associated with troublesome side-effects including sedation, seizures, and a small but significant rate of agranulocytosis. These side effects might limit the efficacy when used in routine clinical settings by physicians who have only limited experience with the medication. Dammasch State Hospital has treated 39 patients and provided follow-up data after 10 weeks of treatment. Thirteen patients had BPRS improvement of more than 30%. Oregon State Hospital reported the outcome of 45 patients at 16 weeks, with 9 patients showing “excellent” therapeutic results. Eastern Oregon
Pharmacological
evaluation
of sertindole:
candidates.
(Portions
of this work were
A new atypical neuroleptic
T. Skarsfeldt 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 micromol/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 Weslem 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
327
binding site in vivo. Both typical and atypical APD displaced 5HT-2 binding in vivo in cortex with similar affinities. There were significant positive correlations between the ability of the APD to displace DA-2 receptor binding in vitro and in vivo, and to displace 5HT-2 receptor binding in vitro and in vivo. The typical APD loxapine was more potent in vivo than in vitro in competing for 5HT-2 or DA-2 binding sites. These results indicate that the ratio of potency of APD in displacing DA-2 and 5HT-2 receptor binding both in vivo and in vitro discriminates between typical and atypical APD. The atypical APD may achieve their antischizophrenic action without blocking DA-2 receptors in vivo.
Phase I trials of BMY 14802, a potential antipsychotic sigma binding sites
with affinity for
D.P. Taylor*‘, U.A. Shukla2, S.A. Wolfe, Jr.4, P.Q. Owen3, R. Pyke3, E.B. DeSouza4 ‘CNS Drug Discovery, ‘Metabolism and Pharmacokinetics, and 3CNS Clinical Development, Bristol-Meyers Squibb Pharmaceutical Research Institute, Wallingforrl, CT 06492-7660, U.S.A., and 4AaUiction Research Center, National Institate on DragAbuse, Baltimore, MD 21224, U.S.A.
BMY 14802 has emerged as a potential antipsychotic with a preclinical profile consistent with efficacy comparable to available antipsychotics and with greater apparent safety. It is active in traditional models of antipsychotic efficacy as well as newer models such as the attenuation of behaviors elicited by chronic amphetamine intoxication in monkeys. Its potential for safety in long-term use is suggested by its lack of effect on D-2 dopamine receptors or neuronal activity in the substantia nigra after chronic administration to rats. BMY 14802 exhibits selective affinity for the limbic system in its effects on dopamine and its metabolites, but it does not bind to D-2 or D-l dopamine receptors in vitro or in vivo. BMY 14802 exhibits potent, steroselective competitive inhibition of binding to u sites. The R( + ) enantiomer is more potent at the u site and the 5-HTlA receptor than the S(-) enantiomer. Phase I trials of BMY 14802 have been completed. The first single dose study was carried out in 109 healthy male volunteers. Oral doses ranging from 2 to 800 mg were administered with 6 subjects in each dose group except 4 at 700 and 2 at 800 mg. A safety endpoint was reached at the 800 mg dose. A second 28 day multiple dose, double-blind, placebo-controlled safety, tolerance, and pharmacokinetic study was carried out in 22 healthy volunteers. Oral doses of 200,300,400 and 500 mg were administered on a q.i.d. schedule. The drug was well tolerated with no reportable side effects. In particular, no signs of movement disorders were observed. Subjects receiving BMY 14802 had elevated levels of u binding on peripheral blood leucocytes compared to subjects receiving placebo. Leucocyte binding was not correlated with Cm, or AUC values for blood levels of BMY 14802. If BMY 14802 were au “antagonist”, it might be expected that long-term administration of the drug would result in u “supersensitivity.” In fact, Bremer et al. (Sot. Neurosci. Abst. 15: 1216, 1989) have observed this phenomenon with BMY 14802 in the rat. Should future well-controlled clinical trials demonstrate clinical efficacy, BMY 14802 may act by a novel mechanism to treat the symptoms of schizophrenia with reduced liability for the side effects (extrapyramidal side effects, cardiotoxicity, agranulocytosis) of currently-available drugs.
Initial experience with clozapine in Oregon’s State Hospitals W.H. Wilson Department of Psychiatry, Oregon Health Sciences Universily, 3181 S. W. Sam Jackson Park Road, OPO2, Portlanti, OR 97201-3098, USA.
Controlled clinical trials and compassionate use protocols have indicated that clozapine is of significant therapeutic benefit to many individuals with otherwise treatment-resistant schizophrenia, at least when used in these carefully controlled circumstances. Clozapine therapy has been associated with troublesome side-effects including sedation, seizures, and a small but significant rate of agranulocytosis. These side effects might limit the efficacy when used in routine clinical settings by physicians who have only limited experience with the medication. Dammasch State Hospital has treated 39 patients and provided follow-up data after 10 weeks of treatment. Thirteen patients had BPRS improvement of more than 30%. Oregon State Hospital reported the outcome of 45 patients at 16 weeks, with 9 patients showing “excellent” therapeutic results. Eastern Oregon