U-64,273A:
By the intravenous (i.v.) route of administration to anesthetized rats, U-64,273A is potent in reversing the effect of
d-amphetamine on nigral DA neuronal firing. Standard antipsychotic agents such as
haloperidol and
clozapine also reversed amphetamine's depressions of DA neuronal firing, as has been reported by other laboratories (1). The ability of neuroleptics to actually increase firing rates above control values has been associates (1,2) with the tendency of that agent to induce
extrapyramidal side effects (EPS). Thus,
haloperidol, which induces severe
EPS in patients, increased firing rates to a level 64% greater than controls whereas
clozapine, which induces far less
EPS, (3), completely reversed the amphetamine effect but did not increase rates above controls (
Table 2) . Unlike
haloperidol the amphetamine effect reversal by U-64,273A was not quite complete. This suggests that U-64,273A in addition to being a dopamine antagonist has a small amount (partial) of dopamine agonist activity. A partial agonist property is further suggested by the fact that U-64,273 is able to weakly inhibit the DA neuronal firing when given alone. This pattern of effect is similar to that other partial agonists,
trans-dihydrolisuride (TDHL) , and
(-)PPP(4,-5). However, the dopamine antagonist properties of
TDHL and
(-)PPP are much less prominant than with U-64,273A. Thus, U-64,273A is 70% antagonist and 30% agonist while the antagonist/agonist ratios for
TDHL and (-)PPP are approximately 50:50 and 30:70 respectively (
Table 2). In addition the antagonist potency of U-64,273A is considerably greater than that of
clozapine. The dopamine antagonist properties of U-64,273A should be sufficient to antagonize overactive DA systems such as those though to underly schizophrenia. By avoiding a complete blockage, there may be a reduced severity of side-effects such as
pseudo-parkinsonism and
tardive dyskinesia in using this compound as an antipsychotic drug.
Consistant with its having a minor amount of agonist activity, the overall behavioral effects of U-64,273A conform to that of a weak DA antagonist (
Table 3). It antagonized
apomorphine in the following tests: mouse climbing screen, locomotor stimulation in reserpinized mice, emesis in dogs and discriminative effects in monkeys. U-64,273A also antagonized d-amphetamine in the turning behavior of striatal-lesioned rats. However, it did not protect mice from a lethal dose of d-amphetamine nor did it block the stereotypic behaviors produced by
apomorphine. When given by itself, U-64,273A affected locomotor activities in rodents in a way resembling both DA auto-receptor and postsynaptic receptor agonists. It suppressed conditioned avoidance behavior of rats with a limited efficacy. It produced no locomotor stimulation in reserpinized mice.
The effects of U-64,273A on the metabolites of DA and 5-HT in rat brains suggest an antagonist action of DA and an agonist action of 5-HT (
Table 4) . The elevation of HVA was only moderate in comparison to that produced by
haloperidol. It did not increase the plasma level of
prolactin as did haloperidol. Both the HVA and prolactin effects are consistent with the expected low EPS. U-64,273A is relatively weak in the in vitro receptor binding screen but did displace
spiperone in vivo. (The numbers in parenthesis are to References listed below
Table 5 hereinbelow). The dimethylated derivative,
U-65,556, is also of interest because it has antipsychotic activity with little or no propensity to produce EPS since it,
2,3-dihydro-N,N-dimethyl-1H-phenalen-2-amine, like U-64,273A, also reversed amphetamine's depressions of DA neurons without causing firing rates to increase over control.
