D2 partial agonist

Aripiprazole was formulated in the early 1980s to function as a potential dopamine modulator, with both antagonist and agonist activity at the D2 receptor. It is the first D2 partial agonist available for the treatment of schizophrenia and is sometimes referred to as a third-generation antipsychotic. This novel mechanism is... 

Newer drugs (e.g., clozapine, risperidone, and olanzapine) act as antagonists at 5KT2 receptors and j seem to have fewer adverse effects. Aripiprazole is a D2 partial agonist... 

Aripiprazole (Abilify ) is a D2 partial agonist and an atypical antipsychotic agent [1]. 

Extrapyramidal side-effects generally appear with blockade of dopamine D2 receptors in excess of 80%, whereas clinical efficacy in treating psychosis is associated with 60-70% D2 receptor blockade [12]. Recently, a partial agonist for the D2 receptor known as aripiprazole has been developed, which results in approximately 70% antagonism/30% agonism at the D2 receptor. It is an effective antipsychotic, has low risk for extrapyramidal symptoms, and does not cause elevated levels of prolactin as do the full antagonists at D2 receptors. 

Dopamine A few studies have examined the dopaminergic effects of LSD. The affinity of LSD for D2 receptors is similar to its affinity for 5-HT2 sites, and it has a slightly lower affininty for D1 receptors (Watts et al. 1995). LSD has partial agonist effects at D2 receptors as seen in the inhibition of prolactin release (Giacomelli et al. 1998). Neuroleptic drugs are also used clinically to terminate an LSD experience. Thus, the effects of LSD on dopaminergic function may contribute to its hallucinogeinc effects. 

Giacomelli S, Palmery M, Romanelli L, Cheng CY, Silvestrini B. (1998). Lysergic acid diethylamide (LSD) is a partial agonist of D2 dopaminergic receptors and it potentiates dopamine-mediated prolactin secretion in lactotrophs in vitro. Life Sci. 63(3) 215-22. 

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. 

The predominant mechanism by which currently available antipsychotic medications interfere with dopamine activity is by blockade of dopamine receptors on neurons innervated by dopamine nerve terminals. Of the five types of dopamine receptors, all antipsychotics share in common the fact that they block the dopamine type 2 receptor, also known as the D2 receptor, to a varying degree. Some of the atypical antipsychotics also block other dopamine receptors (see Table 13.5). The role of blockade of Dl, D3, D4, and other dopamine receptors in the therapentic effects of antipsychotic drugs remains unclear. Aripiprazole is an exception to this in that it is a partial agonist at the D2 receptor. 

Aripiprazole is the most recently approved atypical antipsychotic. This medication has a high affinity for D2 and D3 receptors, as well as 5-HTand 5-HT2a receptors. Although the mechanism of action is not known, aripiprazole may mediate its effects via a combination of partial agonist activity at the D2 and 5-HTj receptors and antagonist activity at the 5-HT2 receptor. 

Buspirone has selective anxiolytic effects, and its pharmacologic characteristics are different from those of other drugs described in this chapter. Buspirone relieves anxiety without causing marked sedative, hypnotic, or euphoric effects. Unlike benzodiazepines, the drug has no anticonvulsant or muscle relaxant properties. Buspirone does not interact directly with GABAergic systems. It may exert its anxiolytic effects by acting as a partial agonist at brain 5-HTia receptors, but it also has affinity for brain dopamine D2 receptors. Buspirone-treated patients show no... 

Buspirone Mechanism uncertain Partial agonist at 5-HT receptors but affinity for D2 receptors also possible Slow onset (1-2 weeks) of anxiolytic effects t minimal psychomotor impairment—no additive CNS depression with sedative-hypnotic drugs Generalized anxiety states Oral activity forms active metabolite short half-life Toxicity Tachycardia paresthesias t gastrointestinal distress Interactions CYP3A4 inducers and inhibitors... 

These drugs have complex pharmacology but they share a greater ability to alter 5-HT2A-receptor activity than to interfere with D2-receptor action. In most cases, this is accomplished through a partial agonist mechanism. 

Thus, most of the atypical and some typical antipsychotic agents are at least as potent in inhibiting 5-HT2 receptors as they are in inhibiting D2 receptors. The newest, aripiprazole, appears to be a partial agonist of D2 receptors. Varying degrees of antagonism of 0-2 adrenoceptors are also seen with risperidone, clozapine, olanzapine, quetiapine, and aripiprazole. The clinical relevance of these actions remains to be ascertained. 

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