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DU127090: A novel partial dopamine agonist with antipsychotic activity a putative potent full spectrum antipsychotic with low EPS potential
104 10. N e u r o c h e m i s t r y , A n i m a l DU127090: A NOVEL PARTIAL DOPAMINE AGONIST WITH ANTIPSYCHOTIC ACTIVITY A PUTATIVE POTENT FULL SPECTRUM ANTIPSYCHOTIC WITH LOW EPS POTENTIAL
J. Arnt,* M. B. Hesselink, M. Didriksen, J. A. van der Heijden, R. W. Feenstra, C. G. Kruse Lundebeck A/S, Copenhagen, Denmark The effect of DU127090, a novel putative antipsychotic agent was evaluated in a number of preclinical models with predictive value for antipsychotic, antidepressant and anxiolytic action in man. DU127090 has potent antipsychotic-like effects in a therapeutic model sensitive to all antipsychotic agents (suppression of conditioned avoidance behaviour in rats, minimal effective dose (IVIED)for DU127090 0.31 mg/kg sc, MED of haloperidol 0.080 mg/kg sc). Phencyclidine [PCP, a noncompetitive antagonist of N-methyl-Daspartate (NMDA) receptors] induces a psychotomimetic state that has been suggested to be an important pharmacological model of schizophrenia. In rats and mice, PCP induces hyperactivity and stereotypy as well as cognitive deficits. DU127090 inhibited PCPinduced hyperactivity in mice (ED50=0.00096 mg/kg sc), inhibition of baseline activity was seen at much higher doses (ED50=0.083 mg/kg sc). The high potency and selectivity of DU127090 against PCP-induced hyperactivity is unique compared to known antipsychotic drugs. The antipsychotic-like effect of DU127090 in these models is most probably due to its interaction with the dopamine D 2 receptor. Most interestingly, DU127090 contrasts with most existing antipsychotics in that the compound induces certain effects that are typical for both antidepressant and anxiolytic compounds. In a model for antidepressant activity in rats, the differential reinforcement of low rates of responding, DU127090 dose dependently decreased the response rate (LED 0.03 mg/kg ip) and increased the reinforcement rate (LED 0.1 mg/kg ip) of the animals, effects it shares with classic antidepressant drugs. In a model for anxiolytic/antidepressant activity DU 127090 potently suppressed ultrasonic vocalisations in rats exposed to a threatening environment (LED 0.01 mg/kg ip). Haloperidol had no anxiolytic effect in that model (LED>2.0 mg/kg ip). Additionally, DU 127090 sharply contrasts with haloperidol in that it has no cataleptic effect in rats (ED50>16 and 0.15 mg/kg sc respectively). In conclusion, DU127090 is expected to show a full spectrum of antipsychotic, antidepressant and anxiolytic activity, and is likely to be effective in the treatment of both positive and negative symptoms of schizophrenia, combined with a low risk of inducing extrapyramidal side effects.
EFFECTS OF TYPICAL AND ATYPICAL ANTIPSYCHOTICS ON MATERNAL BEHAVIOR IN POSTPARTUM FEMALE RATS R. Budin,* M. Li, R Davidson, A. S. Fleming, S. Kapur Department of Psychology, University of Toronto at Mississauga, Mississauga, ON, Canada Understanding the effects of antipsychotics on social behaviors is critical for understanding the complete spectrum of therapeutic and side-effects of antipsychotics. The present report examined the behavioral effects of typical and atypical antipsychotics on rat maternal behavior, a natural and complex pup-directed social behavior. The typical antipsychotic haloperidol (0.02, 0.1 and 0.2 mg/kg) and
three current atypical antipsychotics: risperidone (0.2, 0.8 and 2.0 mg/kg), quetifipine (5, 25, and 50 mg/kg) and clozapine (2, 10, and 20 mg/kg)were administered to Day 6-7 postpartum female rats, and their maternal behaviors were examined 7 times over a period of 24 hours. All antipsychotic drugs exhibited a qualitatively similar disruptive function on the active components of maternal behavior such as pup approach, pup retrieval and nest-building at the clinically-relevant doses (HAL at 0.1 mg/kg, RIS at 0.8 mg/kg, QUE at 25 mg/kg and CLZ at 10 mg&g). In addition, the atypicals showed inconsistent inhibitory effects on nursing behavior, possibly due to their common sedative effects. However, comparable doses of HAL, CLZ, RIS and QUE displayed different temporal characteristics with regard to their effects on maternal behavior: HAL caused a prolonged disruption (more than 6 hrs), whereas CLZ, RIS and QUE induced an early onset but transient disruption (0.5 hr-4 hr), consistent with their differential temporal profiles of dopamine D2 receptor occupancy. It is proposed that maternal deficits induced by sub-cataleptic doses of antipsychotics are likely indicative of the deficits in maternal motivation, and all antipsychotics regardless of their different chemical structures or type (i.e. typical or atypical) possess this property. Since this attribute of die current antipsychotics is unlikely to have positive consequences for patients, this model of maternal behavior may also serve as a model of deficits that may be avoided in future antipsychotics.
INHIBITION OF PSYCHOSTIMULANTINDUCED HYPERACTIVITY RESPONSES IN RATS FOLLOWING ORAL ADMINISTRATION OF THE METABOTROPIC GLUTAMATE RECEPTOR 2/3 AGONISTS, LY379268 AND MGS0028 U. C. Campbell,* D. Rodriguez, A. Nakazato, S. Chaki, L. Bristow Behavioral Pharmacology, Merck Research Laboratories, San Diego, CA, USA The distribution, function and modulatory role of group 2 metabotropic glutamate receptors (mGluR2/3) indicate that these receptors may be an important target for the treatment of schizophrenia. The antipsychotic potential of mGluR2/3 agonists has largely been examined in vivo using rodent models of psychostimulantinduced hyperactivity. Although several studies have shown that selective mGluR2/3 agonists attenuate psychostimulant-induced hyperactivity (Moghaddam and Adams 1998; Cartmell et al. 1999, 2000; Nakazato et al. 2000), other studies have reported no inhibitory effect (Ballard et al. 2001). In the present study, the ability of LY379268 (0.3-10 mg/kg, PO) and MGS0028 (0.3-3 mg/kg, PO)(potent, selective and orally active mGluR2/3 agonists) to block the hyperactivity responses induced by various psychostimulants (i.e., amphetamine and the non-competitive NMDA receptor antagonists, phencyclidine (PCP) and ketamine) was further evaluated. Amphetamine (3 mg/kg, SC), PCP (5 mg/kg, SC) and ketamine (25 mg/kg, SC) hyperactivity responses were dose-dependently reduced by LY379268 (ED50 = 1.5, 3.3 and 1.4 mg/kg, respectively) and MGS0028 (ED50 = (0.3 mg/kg for all psychostimulants). Similar to established antipsychotics, both compounds also dose-dependently reduced spontaneous locomotor activity at doses comparable to those inhibiting psychostimulant-induced hyperactivity. Results from these studies indicate that 1) the mGluR2/3 agonists, LY379268 and MGS0028, produce behavioral effects suggestive of antipsychotic
International Congress on Schizophrenia Research 2003
J. Arnt,* M. B. Hesselink, M. Didriksen, J. A. van der Heijden, R. W. Feenstra, C. G. Kruse Lundebeck A/S, Copenhagen, Denmark The effect of DU127090, a novel putative antipsychotic agent was evaluated in a number of preclinical models with predictive value for antipsychotic, antidepressant and anxiolytic action in man. DU127090 has potent antipsychotic-like effects in a therapeutic model sensitive to all antipsychotic agents (suppression of conditioned avoidance behaviour in rats, minimal effective dose (IVIED)for DU127090 0.31 mg/kg sc, MED of haloperidol 0.080 mg/kg sc). Phencyclidine [PCP, a noncompetitive antagonist of N-methyl-Daspartate (NMDA) receptors] induces a psychotomimetic state that has been suggested to be an important pharmacological model of schizophrenia. In rats and mice, PCP induces hyperactivity and stereotypy as well as cognitive deficits. DU127090 inhibited PCPinduced hyperactivity in mice (ED50=0.00096 mg/kg sc), inhibition of baseline activity was seen at much higher doses (ED50=0.083 mg/kg sc). The high potency and selectivity of DU127090 against PCP-induced hyperactivity is unique compared to known antipsychotic drugs. The antipsychotic-like effect of DU127090 in these models is most probably due to its interaction with the dopamine D 2 receptor. Most interestingly, DU127090 contrasts with most existing antipsychotics in that the compound induces certain effects that are typical for both antidepressant and anxiolytic compounds. In a model for antidepressant activity in rats, the differential reinforcement of low rates of responding, DU127090 dose dependently decreased the response rate (LED 0.03 mg/kg ip) and increased the reinforcement rate (LED 0.1 mg/kg ip) of the animals, effects it shares with classic antidepressant drugs. In a model for anxiolytic/antidepressant activity DU 127090 potently suppressed ultrasonic vocalisations in rats exposed to a threatening environment (LED 0.01 mg/kg ip). Haloperidol had no anxiolytic effect in that model (LED>2.0 mg/kg ip). Additionally, DU 127090 sharply contrasts with haloperidol in that it has no cataleptic effect in rats (ED50>16 and 0.15 mg/kg sc respectively). In conclusion, DU127090 is expected to show a full spectrum of antipsychotic, antidepressant and anxiolytic activity, and is likely to be effective in the treatment of both positive and negative symptoms of schizophrenia, combined with a low risk of inducing extrapyramidal side effects.
EFFECTS OF TYPICAL AND ATYPICAL ANTIPSYCHOTICS ON MATERNAL BEHAVIOR IN POSTPARTUM FEMALE RATS R. Budin,* M. Li, R Davidson, A. S. Fleming, S. Kapur Department of Psychology, University of Toronto at Mississauga, Mississauga, ON, Canada Understanding the effects of antipsychotics on social behaviors is critical for understanding the complete spectrum of therapeutic and side-effects of antipsychotics. The present report examined the behavioral effects of typical and atypical antipsychotics on rat maternal behavior, a natural and complex pup-directed social behavior. The typical antipsychotic haloperidol (0.02, 0.1 and 0.2 mg/kg) and
three current atypical antipsychotics: risperidone (0.2, 0.8 and 2.0 mg/kg), quetifipine (5, 25, and 50 mg/kg) and clozapine (2, 10, and 20 mg/kg)were administered to Day 6-7 postpartum female rats, and their maternal behaviors were examined 7 times over a period of 24 hours. All antipsychotic drugs exhibited a qualitatively similar disruptive function on the active components of maternal behavior such as pup approach, pup retrieval and nest-building at the clinically-relevant doses (HAL at 0.1 mg/kg, RIS at 0.8 mg/kg, QUE at 25 mg/kg and CLZ at 10 mg&g). In addition, the atypicals showed inconsistent inhibitory effects on nursing behavior, possibly due to their common sedative effects. However, comparable doses of HAL, CLZ, RIS and QUE displayed different temporal characteristics with regard to their effects on maternal behavior: HAL caused a prolonged disruption (more than 6 hrs), whereas CLZ, RIS and QUE induced an early onset but transient disruption (0.5 hr-4 hr), consistent with their differential temporal profiles of dopamine D2 receptor occupancy. It is proposed that maternal deficits induced by sub-cataleptic doses of antipsychotics are likely indicative of the deficits in maternal motivation, and all antipsychotics regardless of their different chemical structures or type (i.e. typical or atypical) possess this property. Since this attribute of die current antipsychotics is unlikely to have positive consequences for patients, this model of maternal behavior may also serve as a model of deficits that may be avoided in future antipsychotics.
INHIBITION OF PSYCHOSTIMULANTINDUCED HYPERACTIVITY RESPONSES IN RATS FOLLOWING ORAL ADMINISTRATION OF THE METABOTROPIC GLUTAMATE RECEPTOR 2/3 AGONISTS, LY379268 AND MGS0028 U. C. Campbell,* D. Rodriguez, A. Nakazato, S. Chaki, L. Bristow Behavioral Pharmacology, Merck Research Laboratories, San Diego, CA, USA The distribution, function and modulatory role of group 2 metabotropic glutamate receptors (mGluR2/3) indicate that these receptors may be an important target for the treatment of schizophrenia. The antipsychotic potential of mGluR2/3 agonists has largely been examined in vivo using rodent models of psychostimulantinduced hyperactivity. Although several studies have shown that selective mGluR2/3 agonists attenuate psychostimulant-induced hyperactivity (Moghaddam and Adams 1998; Cartmell et al. 1999, 2000; Nakazato et al. 2000), other studies have reported no inhibitory effect (Ballard et al. 2001). In the present study, the ability of LY379268 (0.3-10 mg/kg, PO) and MGS0028 (0.3-3 mg/kg, PO)(potent, selective and orally active mGluR2/3 agonists) to block the hyperactivity responses induced by various psychostimulants (i.e., amphetamine and the non-competitive NMDA receptor antagonists, phencyclidine (PCP) and ketamine) was further evaluated. Amphetamine (3 mg/kg, SC), PCP (5 mg/kg, SC) and ketamine (25 mg/kg, SC) hyperactivity responses were dose-dependently reduced by LY379268 (ED50 = 1.5, 3.3 and 1.4 mg/kg, respectively) and MGS0028 (ED50 = (0.3 mg/kg for all psychostimulants). Similar to established antipsychotics, both compounds also dose-dependently reduced spontaneous locomotor activity at doses comparable to those inhibiting psychostimulant-induced hyperactivity. Results from these studies indicate that 1) the mGluR2/3 agonists, LY379268 and MGS0028, produce behavioral effects suggestive of antipsychotic
International Congress on Schizophrenia Research 2003