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The psychoses affect approximately 1% of the population in all cultures. They are psychogenic mental disorders involving a loss of contact with reality. The psychotic disorders include schizophrenia, the manic phase of bipolar (manic-depressive) illness, acute idiopathic psychotic illness, and other conditions marked by severe agitation. The most common is schizophrenia, in which perception, thinking, communication, social functioning, and attention are altered.

Schizophrenia is a particular kind of psychosis characterized mainly by a clear sensorium but a marked thinking disturbance. Symptoms are called positive (e.g., delusions, hallucinations) or negative (e.g., flat affect, apathy); cognitive dysfunction may occur. In the schizophrenias, which have an extremely complex and multifactored etiology,22,23 the fundamental lesion appears to be a defect in the brain's informational gating mechanism. Basically, the gating system has difficulty discriminating between relevant and irrelevant stimuli. The etiology of psychosis remains unknown, although genetic, neurodevelopmental and environmental causative factors have all been proposed. Psychoses can be organic and related to a specific toxic chemical (e.g., delirium produced by central anticholinergic agents), an N-methyl D-aspartate (NMDA) receptor antagonist (e.g., phencyclidine [PCP]), a definite disease process (e.g., dementia), or they can be idiopathic.

Although the actual structural or anatomical lesions are not known, the basic defect appears to involve overactivity of dopaminergic neurons in the mesolimbic system. DA hypothesis for schizophrenia is the most fully developed of several hypotheses and is the basis for much of the rationale for drug therapy because (a) drugs that increase dopaminergic neurotransmission, such as levodopa (a DA precursor), amphetamines (a DA releaser), and apomorphine (a DA agonist), induce or exacerbate schizophrenia. Amphetamine-induced psychosis was determined to be caused by overacti-vation of mesolimbic D2 receptors and judged to be the closest of the various chemically induced model psychoses to the schizophrenias; (b) DA receptor density is increased in certain brain regions of untreated schizophrenics; (c) many antipsychotic drugs strongly block postsynaptic D2 receptors in CNS; and (d) successful treatment of schizophrenic patients has been reported to change the amount of homovanil-lic acid (HVA), a DA metabolite, in the cerebrospinal fluid, plasma, and urine. Consequently, the antipsychotic action is now thought to be produced (at least in part) by their ability to block DA receptors in the mesolimbic and mesofrontal systems. Moreover, extrapyramidal side effects of antipsychotic drugs correlate with their D2 antagonism effect. The hyper-prolactinemia that follows treatment with antipsychotics is caused by blockade of DA's tonic inhibitory effect on pro-lactin release from the pituitary. Nevertheless, the defects of DA hypothesis are significant, and it is now appreciated that schizophrenia is far more complex than originally supposed. Several classes of drugs are effective for symptomatic treatment.

Interest in DA, 5-HT, and Glu NTs led to most early drugs targeting the DA system, primarily as DA D2 receptor. Typical antipsychotics (e.g., chlorpromazine, haloperidol) are better for treating positive signs than negative signs. For treating negative signs, the newer (atypical) antipsychotic drugs (e.g., clozapine, risperidone) target D2 receptor and other receptors. The bases of the atypical group's activity against negative symptoms may be serotonin-2A receptor (5-HT2A) block, block at receptors yet to be determined, and possibly decreased striatal D2 block.24 A classic competitive antagonism has been demonstrated at D2 and D3 receptors. Also, in recombinantly expressed receptors, inverse agonism has been demonstrated. Recent studies show that essentially all clinically used antipsychotic drugs are D2 inverse agonists, suggesting that biochemical as well as clinical effects may not be explained by simple D2 receptor blockade hypothesis.25

Typical antipsychotics began with the serendipitous discovery of the antipsychotic activity of chlorpromazine. A clear association between the ability to block DA at mesolimbic D2 receptors was established. The conventional typical antipsychotics (neuroleptics) are characterized by the production of EPS, roughly approximating the symptoms of Parkinson disease. These are reversible on discontinuing or decreasing the dose of the drug and are associated with blockade of DA at D2 striatal receptors. After sustained high-dose therapy with antipsychotics, a late-appearing EPS, tardive dyskinesia, may occur. The overall symptomatology resembles the symptoms of Huntington chorea. Atypical antipsychotics date from the discovery of clozapine, its antipsychotic properties, and its much lower production of EPS. Also contributing to the development of atypical antipsychotics was the introduction of risperidone. It has reduced EPS, has increased activity against negative symptoms, and, in addition to its DA-blocking ability, is a 5-HT2A antagonist. The view has been proposed that 5-HT2A receptors are involved in part (the negative symptoms) or wholly in schizophrenia. So far, the evidence appears to be that 5-HT2A blocking agents do not relieve positive effects of schizophrenia.24 The view that 5-HT2A overactivity is the source of negative symptoms (part of the basis of psychosis) is not disproved at present, although some say it has been weakened.24

One result of the development of atypical antipsychotics has been a renewed interest in models of psychosis other than the amphetamine model. In line with possible dual involvement of 5-HT and DA, the lysergic acid diethylamide (LSD, a 5-HT agonist) model has been cited as better fitting schizophrenias than the amphetamine model. However, this has been disputed. Interest in serotoninergic involvement is still high and involves elucidating the roles of 5-HT6 and 5-HT7 receptors.

Interest remains in understanding the psychosis produced by several central anticholinergics. Muscarinic (M1 and M4) agonists appear to offer the best approach at this time.26 The role of the M5 receptor awaits synthesis of M5-specific drugs.27

PCP (an NMDA antagonist)-induced psychosis has been proposed as a superior model for schizophrenia, because it presents both positive and negative symptoms.24 It suggests that deficits in glutaminergic function occur in schizophrenia. Results of agonists of NMDA receptors, overall, have not been productive because of the excitatory and neuro-toxic effects of the agents tested. Identification of susceptible receptor subtypes as targets, using glycine modulation or group II metabotropic receptor agonists to modulate NMDA receptors, has been proposed to circumvent the problems associated with the NMDA agonists.

The ionotropic glutamic acid a-amino-3-hydroxy-5-methyl-4-isoxazole propionic acid (AMPA) receptors are activated by brain-penetrating ampakines. There are suggestions that these agents exert some antipsychotic actions by increasing glutaminergic activity.

The individual antipsychotic agents are now considered. The substituted DA motif is useful as an organizational device. Antipsychotics can be classified into four groups (Table 12.2).


Several dozen phenothiazine antipsychotic drugs are chemically related agents used worldwide. Other phenothiazines are marketed primarily for their antiemetic, antihistaminic, or anticholinergic effect. The large body of information permits accurate statements about the structural features associated with activity (see Fig. 12.5). Many of the features were summarized and interpreted by Gordon et al.28 Phenothiazines have a tricyclic structure (6-6-6 system) in which two benzene rings are linked by a sulfur and a nitrogen atom. The best position for substitution is the 2-position. Activity increases (with some exceptions) as

TABLE 12.2 Classification of Antipsychotics

Drug Groups

Structure Features




Aliphatic side chain Piperidine side chain Piperazine side chain



Least potent and I EPS

More potent and more EPS


Double bond on C10


Less potent than other phenothiazines


Aromatic butylpiperidines and diphenylbutylpiperidines


More potent Fewer autonomic SEs Greater EPS

Newer drugs




Also good for negative symptoms

electron-withdrawing ability of the 2-substituent increases (e.g., chlorpromazine vs. promazine). Another possibly important structural feature in the more potent compounds is the presence of an unshared electron pair on an atom or atoms of the 2-substituent. Substitution at the 3-position can improve activity over nonsubstituted compounds but not as significantly as substitution at the 2-position. Substitution at position 1 has a deleterious effect on antipsychotic activity, as does (to a lesser extent) substitution at the 4-position.

The significance of these substituent effects could be that the hydrogen atom of the protonated amino group of the side chain H-bonds with an electron pair of an atom of the 2-substituent to develop a DA-like arrangement.

Horn and Snyder,29 from x-ray crystallography, proposed that the chlorine-substituted ring of chlorpromazine base could be superimposed on the aromatic ring of DA base, with the sulfur atom aligned with the ^-hydroxyl group of DA and the aliphatic amino groups of the two compounds also aligned. The model used here is based on the interpretation of the SARs by Gordon et al.28 and on the Horn and Snyder29 proposal but involves the protonated species rather than the free base. The effect of the substituent at the 1-position might be to interfere with the side chain's ability to bring the protonated amino group in proximity with the 2-substituent. In the Horn and Snyder29 scheme, the sulfur atom at position 5 is in a position analogous to the ^-hydroxyl group of DA, and it was also assigned a receptor-binding function by Gordon et al.28 A substituent at position 4 might interfere with receptor binding by the sulfur atom.

The three-carbon chain between position 10 and the aliphatic amino nitrogen is critical for neuroleptic activity. Shortening or lengthening the chain at this position drastically decreases the activity. The three-atom chain length may be necessary to bring the protonated amino nitrogen in proximity with the 2-substituent. Shortening the chain to two carbons has the effect of amplifying the antihistaminic and anticholinergic activities. For example, promethazine is effective antihistamine, whereas the amino ethyl derivatives diethazine (anticholinergic) and ethopropazine (antimus-carinic) have proved useful in the treatment of Parkinson disease. The amine is always tertiary. n-dealkylation of the side chain or increasing the size of amino n-alkyl substituents reduces antidopaminergic and antipsychotic activity.

As expected, branching with large groups (e.g., phenyl) decreases activity, as does branching with polar groups. Methyl branching on the ^-position has a variable effect on activity. More importantly, the antipsychotic potency of levo (the more active) and dextro isomers differs greatly. This has long been taken to suggest that a precise fit (i.e., receptor site occupancy) is involved in the action of these compounds.

Decreases in size from a dimethylamino group (e.g., going to a monomethylamino) greatly decrease activity, as do effective size increases, such as the one that occurs with n,n-diethylamino group. Once the fundamental requirement of an effective size of about that equivalent to a dimethyl-amino is maintained, as in fusing n,n-diethyl substituents to generate a conformational restricted pyrrolidino group, activity can be enhanced with increasing chain length, as in n2-substituted piperizino compounds.

The critical size of groups on the amino atom suggests the importance of the amino group (here protonated) for receptor attachment. The effect of the added chain length, once the critical size requirement is met, could be increased affinity. It appears to have been reasonably proved that the

3-atom chain betwen 2 Ns is optimal

Figure 12.5 • SAR of phenothiazine antipsychotic agents.

Sar Phenothiazine

protonated species of the phenothiazines can bind to DA

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