PD 158771, a potential antipsychotic agent with D2/D3 partial agonist and 5-HT(1A) agonist actions. II. Preclinical behavioral effects.

PD 158771 has been described in receptor binding and biochemical tests as a partial agonist at dopamine (DA) D2 and D3 receptors as well as an agonist at serotonin (5-HT)(1A) receptors. The present studies describe the profile of PD 158771 in rodent and primate behavioral tests. PD 158771 reduced spontaneous locomotor activity in mice (ED(50)=0.38 mg/kg, i.p.) and rats (ED(50) = 1.2 mg/kg, i.p. and 0.16 mg/kg, s.c.), and reduced amphetamine-stimulated locomotion in mice (ED(50) = 0.13 mg/kg, i.p.). At relatively higher doses up to 3 mg/kg, s.c. in rats, PD 158771 did not produce locomotor stimulation or induce stereotypy, indicating a lack of postsynaptic DA agonist activity. PD 158771 reduced apomorphine stimulated locomotion in rats at a dose 4.6-fold greater than those that reduced spontaneous locomotor activity, indicating weak postsynaptic DA antagonist actions; results consistent with a partial agonist profile. PD 158771 produced anxiolytic-like effects in the water-lick (Vogel) conflict test, effects possibly due to the 5-HT(1A) activity. However, PD 158771 was inactive in the water wheel behavioral despair model in rats, indicating lack of antidepressant properties. Similar to known antipsychotics, PD 158771 produced a potent and long-lasting inhibition of conditioned avoidance responding in squirrel monkeys. In contrast to standard antipsychotics, and similar to clozapine, PD 158771 did not cause catalepsy in rats at a dose 20-fold higher than the ED(50) dose for locomotor inhibition. PD 158771 also had a somewhat lower liability than haloperidol to produce extrapyramidal dysfunction in squirrel and cebus monkeys sensitized to the dystonic effects of haloperidol. The data indicate that PD 158771 is a DA partial agonist with weak intrinsic activity that selectively activates brain DA autoreceptors. PD 158771 produced behavioral effects consistent with potential antipsychotic and anxiolytic efficacy, and has an improved profile in the extrapyramidal side effect model when compared to certain currently available antipsychotic agents.

Pharmacokinetics and pharmacodynamics of an investigational antipsychotic agent, CI-1007, in rats and monkeys.

PURPOSE: To study the pharmacokinetics (PK) and pharmacodynamics (PD) of an investigational antipsychotic agent, CI-1007, in rats and monkeys. METHODS: CI-1007 and a pharmacologically active metabolite, PD 147693 (M1), were evaluated in animal antipsychotic tests (inhibition of dopamine neuron firing and spontaneous locomotor activity in rats, and inhibition of continuous avoidance in monkeys). Plasma concentrations of CI-1007 and M1 were determined using validated HPLC assays. Log-linear and link models were used for PK/PD analysis. RESULTS: CI-1007 and M1 have shown similar effects on dopamine neuron firing (2.5 mg/kg i.p.), and produced dose-related effects on spontaneous locomotor activity in rats (0.3-30 mg/kg p.o.) and on continuous avoidance in monkeys (0.6-1.2 mg/kg p.o.). After pharmacologically active CI-1007 doses, mean plasma CI-1007 Cmax increased from 19 to 200 ng/ml in Sprague-Dawley rats at doses of 3-30 mg/ kg, and from 8.1 to 34 ng/ml in squirrel monkeys at doses of 0.6-1.2 mg/kg, but corresponding plasma M1 Cmax values were near or below the limit of quantitation (5 ng/ml). CI-1007 EC50 was 31.1 ng/ml in rats, calculated from a long-linear regression. In monkeys, CI-1007 ECe50, gamma, and Keo at 0.6 and 1.2 mg/kg were 4.8 and 4.5 ng/ml, 1.9 and 2.0, and 0.47 and 0.48 hr-1, respectively, calculated by the link model. CONCLUSIONS: CI-1007 has shown dose-related pharmacokinetics and pharmacodynamics in rats and monkeys. Although M1 produces antipsychotic-like effects similar to CI-1007, the contribution of M1 to the activity of the parent drug may not be significant in rats and monkeys as based on plasma levels. CI-1007 plasma concentration correlates log-linearly with inhibition effect from the rat locomotor study. The counter-clockwise hysteresis relationship of CI-1007 plasma concentration and inhibition effect from the monkey avoidance test was described by a link model, and the resulting Ce (concentration in effect compartment) versus effect profile exhibits a sigmoidal curve.

The pharmacology of the novel and selective sigma ligand, PD 144418.

The pharmacology of PD 144418 (1-propyl-5-(3-p-tolyl-isoxazol-5-yl)-1,2,3,6-tetrahydropyridine) was characterized using neurochemical, biochemical and behavioral techniques. For sigma (sigma 1 and sigma 2 respectively) sites, PD 144418 affinities were determined using whole guinea pig brain membranes with [3H](+)-pentazocine and neuroblastoma x glioma cell membranes using [3H]1,3,di-O-tolylguanidine (DTG) in the presence of 200 nM (+)-pentazocine. PD 144418 exhibited an affinity for sigma 1 of 0.08 nM (Ki) versus a K1 of 1377 nM for sigma 2 site. Additional receptor binding studies indicated that PD 144418 lacked affinity for dopaminergic, adrenergic, muscarinic and a variety of other receptors. In vitro studies indicated that PD 144418 reversed the N-methyl-D-aspartate (NMDA)-induced increase in cyclic GMP (cGMP) in rat cerebellar slices without affecting the basal levels, suggesting that sigma 1 sites may be important in the regulation of glutamine-induced actions. PD 144418 potentiated the decrease in 5-hydroxytryptophan caused by haloperidol in the mesolimbic region, but by itself had no effect in 5-hydroxytrypamine (5-HT) and dopamine (DA) synthesis. Behaviorally, similar to other sigma ligands, PD 144418 antagonized mescaline-induced scratching at doses that did not alter spontaneous motor activity. This action is suggestive of potential antipsychotic property. It exhibited no anxiolytic and antidepressant properties in the models used. These results show that PD 144418 is a very selective sigma 1 agent, devoid of any significant affinity for other receptors and that sigma 1 site may modulate actions in the CNS.

CI-1007, a dopamine partial agonist and potential antipsychotic agent. II. Neurophysiological and behavioral effects.

CI-1007 has been described in receptor binding and biochemical tests as a dopamine (DA) partial agonist that exhibits DA autoreceptor agonist effects. The present studies describe the profile of CI-1007 in electrophysiological and behavioral tests. CI-1007 inhibited the firing of substantia nigra DA neurons with intrinsic DA agonist activity that was less than that of the full agonists apomorphine and talipexole but greater than that of the weak partial agonist SDZ 208-912. CI-1007 was more potent after intracerebroventricular versus intraperitoneal injection in inhibiting spontaneous locomotor activity in mice, indicating a central site of action. In rats, CI-1007 inhibited locomotor activity after i.v. and p.o. injection, but did not produce locomotor stimulation or induce stereotypy, indicating a lack of postsynaptic DA agonist activity. The relative potencies of CI-1007 for inhibiting apomorphine-stimulated behaviors versus spontaneous locomotor activity in rodents indicated weak postsynaptic DA antagonist actions, consistent with a partial agonist profile. Similar to known antipsychotics, CI-1007 potently inhibited Sidman avoidance responding in squirrel monkeys, but, in contrast to most available antipsychotics, CI-1007 caused only mild extrapyramidal dysfunction in squirrel and cebus monkeys sensitized to the dystonic effects of haloperidol. These data indicate that CI-1007 is a DA partial agonist of moderate intrinsic activity that activates brain DA autoreceptors, produces behavioral effects predictive of antipsychotic efficacy and has a low liability for induction of extrapyramidal side effects.

Pharmacological profile of the dopamine partial agonist, (+/-)-PD 128483 and its enantiomers.

(+/-)-PD 128483, ((+/-)-4,5,5a,6,7,8-hexahydro-6-methylthiazolo[4,5-f]-quinolin+ ++-2-amine, maleate (1:1)), is a racemic compound that is a p.o. active dopamine (DA) partial agonist that has DA autoreceptor agonist effects and displays antipsychoticlike activity in preclinical tests. In in vitro receptor binding assays, (+/-)-PD 128483 and its enantiomers bound selectively to DA D-2 receptors vs. DA D-1 receptors and showed no affinity for adrenergic alpha-1 or serotonin1A receptors, but had affinity for adrenergic alpha-2 receptors. In tests of DA agonist effects, including reversal of the tau-butyrolactone-stimulated increase in brain dopa synthesis in striatum and inhibition of DA neuronal firing, the rank order of efficacy was (+)-PD 128483 > (+/-)-PD 128483 > (-)-PD 128483. (+/-)-PD 128483 and (+)-PD 128483 inhibited, whereas (-)-PD 128483 increased, brain DA synthesis in normal rats. (+/-)-PD 128483 and (-)-PD 128483 inhibited spontaneous locomotion in rats and did not produce locomotor stimulation or stereotypies. In contrast, (+)-PD 128483 inhibited locomotor activity at low doses, but at relatively high doses increased locomotion and induced stereotypy in rats. (-)-PD 128483 consistently inhibited Sidman avoidance responding in squirrel monkeys. (+/-)-PD 128483 inhibited Sidman avoidance responding in one group of monkeys, but had minimal effects in another group. (+)-PD 128483 did not inhibit avoidance responding. In squirrel or cebus monkeys sensitized to the acute dystonic effects of haloperidol, only (-)-PD 128483 induced extrapyramidal dysfunction. These results indicate that (+/-)-PD 128483 is a DA partial agonist which produces DA autoreceptor agonist effects and has a preclinical behavioral profile suggestive of antipsychotic activity.

Growing familiarity with the test situation augments the vigilance deficit of aged rats.

Quantitative EEG profiles of aged and of young-adult Fisher-344 rats were studied over 10 consecutive recording (3 h) sessions. The individual recording sessions were spaced regularly over a 6-week period. In the aged rats, in recordings from both the frontal cortex and dorsal hippocampus, the EEG characteristics of a vigilance deficit state increased in prominence up through 8 recording sessions before a stable level was reached. A similar trend was not seen in the young-adult rats; instead, these rats showed a stable level of spectral voltage output in both leads over the entire period of the 10 recording sessions. Thus, the aged rat brain appears to suffer from a vigilance deficit state which is revealed most clearly by testing under the basal conditions brought about by thoroughly familiarizing the subjects with the test environment.

Arousal deficit shown in aged rat's quantitative EEG and ameliorative action of pramiracetam compared to piracetam.

The basal EEG profile of the aged Fisher-344 rat was consistently different from that of the young rat, showing dominant high voltage slow-wave components. These slow waves were present in both the frontal cerebral cortex and dorsal hippocampus. Absent or greatly attenuated in the aged rat's hippocampal EEG was rhythmic theta activity, which was always dominant in the young awake rat's hippocampus. These EEG differences were clearly apparent only under basal test conditions, i.e., following habituation to the test situation. Pramiracetam sulfate acted strongly to normalize the aged rat's EEG, while the action of piracetam was weak and appeared to undergo tolerance development.

Pharmacologic therapeutic window of pramiracetam demonstrated in behavior, EEG, and single neuron firing rates.

Following oral or intravenous administration, a representative cognition activator drug, pramiracetam sulfate, is shown to have a pharmacologic therapeutic window at three different levels of study: learned behavior, gross EEG activity of the frontal cortex and hippocampus, and firing rate of single hippocampal neurons.