D1a

D1B/D5

D2long/short

The classical "Dj" receptor; selective antagonists neglected as putative antipsychotics Novel site with low density, corticolimbic localization; no specific function(s) or selective antagonist yet known

The classical "D2" isomorphs; reliable correlation between D2

affinity and neuroleptic potency Novel site with low density, corticolimbic localization; no specific function(s) or selective antagonist yet known Novel site with low density, corticolimbic localization; no specific function(s) or selective antagonist yet known, but blocked "preferentially" by clozapine the dopamine hypothesis of schizophrenia which postulated that psychosis was associated with an increase in dopaminergic function in the brain and that neuroleptics alleviate the symptoms of the illness by blocking the receptors that are specifically activated by dopamine. Later, during the 1970s, it was shown that the antipsychotic action of neuroleptics was correlated with their affinity to block dopamine receptors in vitro. It was discovered, by Kebabian and Calne in 1979, that dopamine receptors could be classified into two specific types, Dx and D2, and that there was a good correlation between the therapeutic potency of the phenothiazine neuroleptics and haloperidol and their affinity for the D2 receptors. With the introduction of molecular cloning techniques it has now been possible to define at least five distinct subtypes of the dopamine receptor in the human brain as well as two variants (termed isoforms) of the original D2 receptor. These different subtypes of the dopamine receptor may be broadly classified into those resembling the original Dj receptor (Dj and D5) and those resembling the D2 receptor (D2, D3 and D4).

The neuroleptics that are widely available may be divided into two general categories, those with low potency (such as chlorpromazine and thioridazine) and those with high potency (exemplified by haloperidol, trifluoperazine and pimozide). The former groups have a lower propensity to cause extrapyramidal side effects but are more sedative and likely to cause postural hypotension and have anticholinergic side effects. In vitro studies have shown that chlorpromazine has an affinity for all five types of dopamine receptor and has some preference for D2 and D3 receptors. By contrast, haloperidol is more potent than chlorpromazine for the D2, D3 and D4 receptors with a low affinity for the D1 and D5 receptors.

In addition to their affinity for dopamine receptors, which appears to be essential for their therapeutic activity, all neuroleptics in current clinical use have affinities for other types of neurotransmitter receptor. Mention has already been made of the side effects of the weaker neuroleptics such as chlorpromazine for histamine-1, muscarinic and alpha-1 adrenoceptors. However, it is now apparent that many of the newer, atypical, neuroleptics have an affinity for subtypes of 5-HT (particularly 5-HT2A) receptors which may be beneficial in reducing the frequency of extrapyramidal side effects. Thus neuroleptics may now be broadly classified into those which are selective antagonists of D2 receptors, those that are D2 and D3 receptor antagonists, those blocking both D1 and D2 receptors and, a most important group of novel neuroleptics, those that are antagonists of 5-HT2 and D2 receptors.

Despite the efficacy of the typical neuroleptics such as chlorpromazine and haloperidol in treating the acute symptoms of schizophrenia, their side effects and failure to treat the negative symptoms emphasized the need to develop atypical antipsychotics. The desirable features of a new anti-psychotic are shown in Table 11.5.

Table 11.5. Desirable features of a new antipsychotic

• Improve positive symptoms in partial and non-responders

• Benefit negative symptoms

• Reduce relapse rates

• Few/no extrapyramidal side effects

• Few adverse effects

• Patient acceptability

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