Benzamide antipsychotics

The atypical antipsychotics are divided into two major pharamacological groups, namely the multiple receptor antagonists, such as clozapine, olanzapine and quetiapine, and the more selective 5-HT2/D2 antagonists as exemplified by risperidone, sertindole, ziprasidone and zotepine. The benzamide antipsychotic amisulpride is the most selective antagonist for the D2/D3 receptors which presumably gives it the mesocortical selectivity of action with a minimal effect on the dopamine receptors in the basal ganglia. 

The origin of the benzamide antipsychotics arose from the astute observation that rodents... 

Reitz AB, Baxter EW, Codd EE, Davis CB, Jordan AD, Maryanoff BE, Maryanoff CA, McDonnell ME, Powell ET, Renzi MJ, Schott MR, Scott MK, Shank RP, Vaught JL. Orally active benzamide antipsychotic agents with affinity for dopamine D2, serotonin 5-HT1A, and adrenergic alphal receptors. J Med Chem 1998 41 1997-2009. 

Chemical ionization can be used at ambient pressures. Chemical ionization was used in tandem MS, using a triple quadrupole instrument, to characterize the antipsychotic agent 2-amino-N(4-(4-(l,2-benzisothiazol-3-yl)-l-piperazinyl)butyl)benzamide from human plasma.5... 

The conventional antipsychotics have little effect on the negative psychotic symptoms such as autism, stupor and emotional withdrawal. The so-called atypical antipsychotics, or second-generation antipsychotics, like the heterocyclic compound risperidone, the benzamide sulpiride and several diben-zepines of which clozapine is the best known, have a broader spectrum which means that they also have an effect on the negative psychotic symptoms. Most share a common attribute of working on serotonin receptors as well as dopamine receptors. They have a low risk of extrapyramidal side effects. 

Benzamides are heterocyclic neuroleptics. These include the gastroenterologic agents metoclopramide and cisapride, which have antiserotonergic as well as anti-D2 receptor dopaminergic actions and also the antipsychotic agents sulpiride and tiapride. Tachyarrhythmias have resulted in the withdrawal of cisapride from general use. 

Tiapride and sulpiride are neuroleptics of the substituted benzamide class. These selective Dj blockers have weak antipsychotic properties and are not available in the United States, although they are commonly used in Europe for the treatment of tics. In a pair of 6-week controlled trials involving 27 children with TS, at doses ranging from 4 to 6 mg/kg/day, tiapride was superior to placebo and produced a 30%-44% decrease in videotaped tic counts (Eggers et ah, 1988). 

The introduction of the phenothiazine derivative, chlorpromazine, has started a dramatic improvement in the clinical treatment of schizophrenia. During the past four decades, beside phenothiazines, various antipsychotics having different chemical structures have been identified and introduced into clinical practice (e.g., butyrophenones and benzamides). These drugs ( typical antipsychotics ) decreased the duration of hospitalizations and, with maintenance treatment, reduced the risk of relapse and re-hospitalization. However, they had significant adverse side effects such as tardive dyskinesia, orthostatic hypotension, prolactin increase, and QT prolongation. 

The example of amisulpride (launched by Sanofi-Synthelabo in 1986) also supports the primary importance of dopamine D2 (as well as D3) but not 5-HT2A receptors in atypical antipsychotic action. This benzamide derivative displays high affinity only to D2 and D3 receptors (with some selectivity toward D3) [42], and in low doses (i.e., 50-100 mg day-1) it acts preferentially on negative [43] symptoms and at higher doses (400-800 mg day-1) on depressive symptoms [44] and cognitive impairment [45]. 

Atypical antipsychotic (benzamide possibly a dopamine stabilizer and dopamine partial agonist)... 

Conventional antipsychotic (neuroleptic, benzamide, dopamine 2 antagonist)... 

Antipsychotics can be divided by chemical class phenothiazines, e.g. chlorpromazine. fluphazine and thioridazine butyrophenones, e.g. haioperidol thioxanthines, e.g. nupenthixol benzamides, e.g. sulpiride diphenylbutyl-piperazines, e.g. pimozide dibenzazepines, e.g. clozapine. None is entirely selective, but in schizophrenia they act mainly at dopamine D2 receptors, though clozapine has important actions at D4 receptors. Those antipsychotics with markedly depressant side-effects are also, somewhat misleadingly, known as major tranquillizers. 

Nembutal sodium pentobarbitone, nemonapride [inn.jan] (YM 09151-2) is a benzamide, a (Dj) DOPAMINE RECEPTOR ANTAGONIST that has been used as an ANTIPSYCHOTIC in the treatment of schizophrenia, neoarsphenamine [inn] is an arsenical with ANTIMICROBIAL activity, used as a veterinary antiinfective and antisyphilitic. 

SUltopride [inn] (sultopride hydrochloride [jan] LIN 1418) is one of the substituted benzamides, with properties similar to sulpiride, and is a dopamine receptor antagonist. It has ANTIEMETIC actions, and has been used as an antipsychotic in the management of acute psychosis, sultopride hydrochloride sultopride. 

Although atypical, sulpiride had relatively low antipsychotic potency (328), possibly because of low bioavailability and poor brain penetration (329). These liabilities, coupled with the apparent atypical profile of sulpiride, spurred research in the benzamide area. 

The present view is that D-2, as a high-affinity species, represents the presynaptic autoreceptor in the CNS. The low-affinity D-2 receptor, then, is postsynaptic. D2 receptors are not coupled to c-AMP as a secondary messenger. Their mass is estimated as 136,700 daltons. The structural variety of D-2 antagonists varies considerably and includes many clinically important groups of antipsychotic drugs the phenothiazine tranquilizers and several of their bioisosteres (the butyrophenones), a dibenzodiazepine (clozapine), the indole derivative molindone, and a benzamide (sulpiride), all to be discussed later. The ergot alkaloids represent D-2 agonists. 

The Mannich reaction between 2-phenylpyrroles and phenylpipera-zines provided Mannich bases as a new class of potential antipsychotics. They served as conformationally restricted benzamide analogues. ... 

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