To the extent that DA overactivity and excessive stimulation of the D2 family of DA receptors are responsible for at least the positive symptom component of schizophrenia, therapeutic avenues other than direct antagonists may be available to modulate these DA neurochemical abnormalities. By exploiting the differential receptor reserve of various tissues and brain regions, it may be possible to use partial agonists of differing intrinsic activity to modulate DA activity. The full spectrum of pharmacology is available for the DA system from full inverse agonists to neutral antagonists to partial agonists to full agonists. Most existing antipsychotic agents are inverse agonists at the D2 receptor family. Regardless of the tissue receptor reserve, inverse agonists will act as antagonists. However, partial agonists have, by definition, lower intrinsic activity. Partial agonists, therefore, can behave as antagonists or agonists depending upon the tissue receptor reserve and their level of intrinsic activity. In tissues with high receptor reserve, these compounds may act as agonists but will act as antagonists in tissues with low receptor reserve.
It is thought that mesolimbic DA systems have low receptor reserve while the mesocortical dopamine system has high receptor reserve. Importantly, D2 autoreceptors are thought to have high receptor reserve. Depending upon the intrinsic activity of an NCE, it should be possible, therefore, for it to act as antagonist in the mesolimbic system in which overactivity is thought to elicit positive symptoms, a weak agonist in the mesocortical system in which reduced DA activity is thought to be associated with heightened negative symptoms and cognitive impairment, and a presynaptic agonist on DA neurons that should reduce dopaminergic neuronal activity and consequently postsynaptic dopamine tone. On theoretical grounds, a partial agonist should be an ideal antipsychotic agent and possess the ability to dynamically modulate dopamine neurotransmission differentially depending upon the state of the dopaminergic tone. The prototypical partial DA agonist, 3-PPP 53, and in particular the S( —)-isomer, (—)-3-PPP, preclamol 54, was the first partial DA agonist to be tested clinically. Patients with schizophrenia appeared to show initial improvements relative to placebo during the first week of therapy but efficacy waned with continued treatment. Other partial DA agonists, including terguride 55, have shown antipsychotic efficacy albeit in small clinical trials.
At least part of the beneficial effects of aripiperazole 5658 may be related to its partial DA agonist properties. As expected of a partial agonist, this drug acts as an antagonist at the D2 receptors in a state of excessive dopaminergic neurotransmission, while it acts as an agonist at the D2 receptor in a state of low dopaminergic neurotransmission. Aripiperazole, therefore, appears to stabilize dopaminergic neurotransmission. However, aripiperazole also exhibits high affinity for serotonin 5HT1A and 5HT2A receptors, moderate affinity for DA D4, 5HT2c and 5HT7, a1-adrenergic and histamine H1 receptors. Thus, its activity as a partial DA agonist must be viewed against the background of other receptor activities. Still, aripiperazole has modest intrinsic activity at DA D2 receptors and this intrinsic activity is less than that of (—)-3-PPP. Aripiperazole has been shown to be effective in treating the symptoms of acutely exacerbated patients with schizophrenia in a series of well-controlled clinical trials. This drug appears to improve both positive and negative symptoms with less risk of eliciting EPS and essentially no propensity for causing hyperprolactinemia (it actually reduces prolactin secretion). This compound also shows a lower risk for weight gain, QTc prolongation, and metabolic side effects.
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