Receptor affinity antipsychotic drugs

Kroeze, W. K., Hufeisen, S. J., Popadak, B. A. et al. HI-histamine receptor affinity predicts short-term weight gain for typical and atypical antipsychotic drugs. Neuropsychopharmacology 28 519-526, 2003. 

It also seems plausible that antipsychotic drugs competitively bind with dopamine receptors and block the action of dopamine on corresponding receptor sites, thus lowering psychotic activity. Central dopamine receptors are subdivided into Dj, D2, and according to some sources, Dj receptors. These receptors have a high affinity for dopamine, but they differ in sensitivity to neuroleptics of various chemical classes. For example, drugs of the phenothiazine series are nonselective competitive Dj and D2 antagonists. Unlike phenoth-iazines, antipsychotics of the butyrophenone series such as haloperidol display selective action only on D2 receptors. 

Five subtypes of dopamine receptors have been described they are the Dj-like and Dj-like receptor groups. All have seven transmembrane domains and are G protein-coupled. The Dj-receptor increases cyclic adenosine monophosphate (cAMP) formation by stimulation of dopamine-sensitive adenylyl cyclase it is located mainly in the putamen, nucleus accumbens, and olfactory tubercle. The other member of this family is the D5-receptor, which also increases cAMP but has a 10-fold greater affinity for dopamine and is found primarily in limbic regions. The therapeutic potency of antipsychotic drugs does not correlate with their affinity for binding to the Dj-receptor. 

Although the traditional neuroleptics do not bind to serotonin (5-MT) receptors with significant affinity, all of the atypical antipsychotics do. This observation has led to the hypothesis that 5-HT receptor blockade is an essential feature of the atypical antipsychotic drugs... 

These findings have been incorporated into the dopamine hypothesis of schizophrenia. However, additional factors complicate interpretation of dopamine receptor data. For example, dopamine receptors exist in both high- and low-affinity forms, and it is not known whether schizophrenia or the antipsychotic drugs alter the proportions of receptors in these two forms. The fact that aripiprazole shows partial agonism at D2 and 5-HT1A receptors in preclinical studies suggests that the proportions of several receptors in their various affinity states may prove clinically important. 

Extension of this specificity principle to the clinical domain has resulted in the availability of increasingly well-aimed chemical bullets. If we wanted to block just one of the many serotonin receptors to see what would happen, we could probably do it But if we wanted to elevate mood in depression—or obsessive-compulsive disorder—would we expect the best result if we blocked just that one receptor And if we wanted to discourage auditory hallucinations in schizophrenia, would we want our drug to target only D2 dopamine receptors, even if we knew that the antipsychotic action of drugs correlated well with a drug s affinity for those receptors ... 

The first generation antipsychotics, now known as typical drugs, were all D2 receptor blockers and, as such, very likely to produce Parkinsonian side effects. Because antipsychotic potency was associated with D2 receptor affinity, it was assumed that dopamine overactivity was the essential defect in schizophrenia and that a direct dopamine blockade was the definitive route to treatment. But these drugs affected both the target dopamine pathways of the mesolimbic projection and the uninvolved nigrostriatal projection. Unfortunately, that meant that movement disorders were the price that had to be paid for antipsychosis. 

A principal interest in our laboratory is the molecular characterization of CNS receptor sites of the neurotransmitter dopamine (DA, 5). These sites are strongly implicated in the biochemical etiology of schizophrenia and Parkinson s Disease, as well as other diseases of the CNS (50,51). Thus, the rank order of clinical potency of antipsychotic drugs (neuroleptics) correlates with the affinity of these drugs for dopaminergic sites (52,53), It is also well established that Parkinson s disease is directly related to deterioration in dopaminergic neurotransmission in the corpus striatum, which is a brain region rich in dopamine receptor sites (54). The use of L-DOPA, the biosynthetic precursor of dopamine, in treatment of patients with Parkinson s disease is one of the best examples of biochemically directed medical treatment. 

Consequently, antipsychotic drugs all share a basic mechanism of action that involves dopamine receptor blockade. It is apparent, however, that they are not all equal in their ability to affect specific sub-types of dopamine receptors, and that their effectiveness and side effects are related to their affinity and preference for certain receptors. As indicated earlier, other neurotransmitters may also be involved in the pathogenesis of psychosis, and differences in specific antipsychotic medications may be related to their ability to directly or indirectly affect these other transmitters as well as block dopamine influence. Future studies will continue to clarify how current antipsychotics exert their beneficial effects and how new agents can be developed to be more selective in their effects on dopamine and other neurotransmitter pathways. 

Table 11.6. Antipsychotic drugs in vitro receptor binding (affinity values K, in...

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