D2 antagonism

Refractory cases respond to clozapine. If D2 antagonism is considered necessary, or at least desirable, for counteracting positive symptoms it is surprising that a relatively weak D2 antagonist like clozapine should not only be so effective but also prove successful in patients who have not responded to other neuroleptics more potent at D2 receptors. 

On this evidence one can confidently equate EPS with neuroleptic DA receptor (D2) antagonism in the striatum and possibly a reduction in the positive symptoms of schizophrenia through similar action in the limbic system (nucleus accumbens). 

The role of these agents, either as primary or adjunctive treatments for mood disorders, has yet to be fully explored ( 106, 108, 279, 280 and 281). Theories have included the differential effects of clozapine on dopamine receptor subtypes (e.g., increased activity at the receptors, which exist in high density in the limbic system) and the greater 5-HT2 to D2 antagonism of most novel agents in comparison with neuroleptics (282). More recently, controlled trials indicate that novel antispychotics (NAPs) may play an important and perhaps unique role for more severe, psychotic, and/or refractory mood disorders ( 112, 283, 384). 

Effects, below. Newer antipsychotics such as olanzapine, quetiapine, and aripiprazole cause no or minimal increases of prolactin and reduced risks of extrapyramidal system dysfunction and tardive dyskinesia, reflecting their diminished D2 antagonism. 

Serotonin 2A antagonism fortunately fails to reverse D2 antagonism in the mesolimbic system. If serotonin 2A antagonism reverses, at least in part, the effects of D2 antagonism in several dopamine pathways, then why does it not reverse the antipsychotic actions of D2 blockade in the mesolimbic dopamine pathway Evidently, the antagonism by serotonin of the effects of dopamine in this pathway is not robust enough to cause the reversal of D2 receptors by atypical antipsychotics or to mitigate the actions of atypical antipsychotics on positive symptoms of psychosis. 

Nowend KL, Arizzi M, Carlson BB, Salamone JD (2001) Dl or D2 antagonism in nucleus accumbens core or dorsomedial shell suppresses lever pressing for food but leads to compensatory increases in chow consumption. Pharmacol Biochem Behav 69 373—382. 

CoMFA results peak at three PLS components for 5FfT1A, in agreement with ALMOND after FFD selection (Table 7). A one-component and a four-component model for D2 antagonism are illustrated for CoMFA with respect to cross-validated predictivity (see Figs. 13 and 14). Both plots indicate a clear separation between active... 

Figure 17 Comparison of stdev coeff CoMFA fields for CoMFA models derived on D2 high (top) and D2 low (middle) activity, and D2 antagonism (low-like) activity (bottom). Compounds are numbered as in Fig. 12. Electrostatic fields are on the left, steric fields on the right. (See color plate at end of chapter.)...

To summarize, the three classes of QSAR models appear to yield comparable results in terms of errors and q2 (except for D2 antagonism), indicating that there is a... 

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