Postsynaptic D2 receptor

An alternative to neuroleptics would be to develop partial DA receptor agonists. Such agonists will preferentially stimulate the sensitive D2 autoreceptors and block the less sensitive postsynaptic D2 receptors. Still, such compounds should have a some degree of intrinsic efficacy for the postsynaptic DA receptors in order not to be cataleptogenic [13]. Neuroleptic-induced catalepsy in rats is considered to be predictive for the precipitation of EPS in the clinic. There are now quite a few partial D2 receptor agonists under clinical evaluation (see below), and the near future will show whether this approach offers some advantage over the classical neuroleptics, which all potently block postsynaptic DA receptors. 

Locomotor activity is measured in motility boxes equipped with photocells. Both horizontal and vertical movements can be registered in the modern boxes. Pretreatment with reserpine (18 h) renders the animals virtually without movement, an akinetic Parkinson-like state. It also makes postsynaptic D2 receptors supersensitive, since the receptors have been exposed to low concentrations of DA for a long period of time. The model is thus useful to reveal D2 agonists with a low degree of intrinsic efficacy and, the intrinsic efficacy of a series of partial agonists can be rated by this model. 

As competitive inhibitors of postsynaptic D2 receptors, neuroleptics decrease dopaminergic input from the substantia nigra and ventral tegmental area into the basal ganglia. 

The actions of amoxapine and maprotiline resemble those of TCAs such as desipramine. Both are potent NET inhibitors and less potent SERT inhibitors. In addition, both possess anticholinergic properties. Unlike the TCAs or other antidepressants, amoxapine is a moderate inhibitor of the postsynaptic D2 receptor. As such, amoxapine possesses some antipsychotic properties. 

FIGURE 11-23. Here postsynaptic dopamine 2 receptors are being blocked by a serotonin-dopamine antagonist (SDA) atypical antipsychotic in the nigrostriatal dopamine pathway. This shows what would happen if only the dopamine 2 blocking action of an atypical antipsychotic were active— namely, the drug would only bind to postsynaptic D2 receptors and block them. However, see Figure 11-24. 

Patients with Parkinson s disease show changes in the pre- and postsynaptic dopaminergic neurons which try to compensate for the progressive disappearance of the transmitter. Thus the surviving pre-synaptic terminals become hyperactive, while the postsynaptic D2 receptors become hypersensitive in an attempt to compensate for the reduced dopaminergic function. These compensatory changes probably account for the relative lack of symptoms of the disease until the dopamine content has been depleted by more than 80%. 

The present view is that D-2, as a high-affinity species, represents the presynaptic autoreceptor in the CNS. The low-affinity D-2 receptor, then, is postsynaptic. D2 receptors are not coupled to c-AMP as a secondary messenger. Their mass is estimated as 136,700 daltons. The structural variety of D-2 antagonists varies considerably and includes many clinically important groups of antipsychotic drugs the phenothiazine tranquilizers and several of their bioisosteres (the butyrophenones), a dibenzodiazepine (clozapine), the indole derivative molindone, and a benzamide (sulpiride), all to be discussed later. The ergot alkaloids represent D-2 agonists. 

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