Antipsychotic activity

Further chemical modification of the phenylpiperidine moiety has proven unusually fruitful in producing medicinal agents that affect the central nervous system. First, a series of compounds loosely related to the reversed meperidines produced several drugs with important antipsychotic activity. Further discussion of this pharmacologic activity, often referred to as major tranquilizer activity, will be found in the section on phenothiazines. The group led by Janssen took advantage of the chemistry of the... 

The use of urethanes of phenothiazines involving the heterocyclic nitrogen (22, 45) as a means of attaching the side chain is discussed above. Although these intermediates apparently do not possess antipsychotic activity, two compounds of this general class, endowed with somewhat more complex appendages, do exhibit... 

As noted earlier (see Chapter 10), 4-acyl piperidines separated from benzimidazole by a three carbon chain often show antipsychotic activity. The heterocycle can apparently be replaced by a pyridopyrimidine ring. Thus alkylation of piperidine 41 with halide 42 affords pirenperone (43). ... 

The breadth of the SAR in the clozapine series is demonstrated by the fact that antipsychotic activity is retained when the dibcnzdiazcpinc nucleus of the parent molecule is replaced by an imidazobenzothiadiazepine ring system which contains twice as many hetero atoms. Preparation... 

The antipsychotic activity of neuroleptics (D2-like receptor antagonists) has led to the development of many different ligands for the D2 receptor. These drugs... 

It is not surprising that a DA antagonist (especially those acting primarily on Di receptors) should produce the symptoms of Parkinsonism, a disorder caused by inadequate DA function (see Chapter 15), nor that its intensity or rate of onset over some weeks or months should increase with Dj antagonistic potency. Tolerance to this adverse effect can develop without affecting antipsychotic activity but the speed with which Parkinsonism resolves after stopping therapy may be from 3 to 12 months and can persist indefinitely in some cases. 

The 5-HT3 receptor is found appropriately in mesocortical areas and while behavioural studies with their antagonists in rodents showed potential antipsychotic activity, they have proved ineffective in patients. 5-HTia agonists may be more useful. They have been found to increase the extracellular concentration of DA in the frontal cortex of rats but diminish apomorphine-induced stereotypy (striatal effect). So they could be of some benefit, especially against negative symptoms, without causing EPSPs (see Chapter 9). 

Robertson, GS, Mastumura, H and Fibiger, HC (1994) Induction patterns of Ebi -like immuno-reactivity in the forebrain as predictors of atypical antipsychotic activity. J. Pharmacol. Exp. Ther. 271 1058-1061 (see also Neuropsychopharmacology 14 105-110). 

Roberts, D.C.S., and Vickers, G. Atypical neuroleptics increase selfadministration of cocaine An evaluation of a behavioral sereen for antipsychotic activity. Psychopharmacology 82 135-139, 1984. 

Roberts D., Vickers G. Atypical neuroleptics increase self-administration of cocaine an evaluation of a behavioral screen for antipsychotic activity. Psychopharmacology. 82 1135, 1984. 

The answer is b. (Hardman, pp 282—283J Central dopamine receptors are divided into Dt and D2 receptors. Antipsychotic activity is better correlated to blockade of D2 receptors. Haloperidol, a potent antipsychotic, selectively antagonizes at Dz receptors. Phenothiazine derivatives, such as chlorpromazine, fluphenazine, and promethazine, are not selective for D2 receptors. Bromocriptine, a selective D2 agonist, is useful in the treatment of parkinsonism and hyperprolactinemia. It produces fewer adverse reactions than do nonselective dopamine receptor agonists... 

Antipsychotic activity Many at5 ical neuroleptics (e.g. amperozide and risperidone) are 5-HT2 receptor antagonists. In animals, 5-HT3 antagonists have profiles similar to chronically active neuroleptics... 

In terms of antipsychotic activity, thioridazine is inferior to aminazine. It is most effective in mental and emotional disorders accompanied by fear, stress, and excitement. It is prescribed for varions forms of schizophrenia, psychosis, and neurosis. The most common synonyms are conapax and mellaril. 

Haloperidol is one of the most actively used modem neuroleptics. Its high antipsychotic activity is combined with a moderate sedative effect. It effectively stops various types of psychomotor excitement. It is used for schizophrenic psychoses, manic, paranoid, and delirious conditions, depression, psychomotor excitement of various origins, and for delirium and hallucinations of different origin. The most common synonyms are haldol, vezadol, linton, and others. 

Buspirone has no established antipsychotic activity do not employ in lieu of appropriate antipsychotic treatment. 

Tiapride has weak antipsychotic activity. It has been used as a adjunct in patients with tardive hyperkinetic syndrome caused by other antipsychotics. 

The large majority of antipsychotic drugs act mainly as dopamine receptor antagonists reducing the excess responsiveness to that neurotransmitter present in psychoses. It was found a decade ago that antagonists of serotonin H2 showed promising antipsychotic activity in several model systems. These dmgs would be better tolerated than their predecessor since they should be devoid of side effects... 

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