Substituents Of Risperidone

Loxapine. A dibenzoxazepine derivative in use is loxapine succinate, 2-chloro-11-(4-methyl-1-piperazinyl)dibenz[b, f ][1,4]oxazepine succinate (Daxolin). The structural relationship to the phenothiazine antipsychotics is apparent. Examples in this group are clothiapine, metiapine, zotepine, and others. They have electron-withdrawing groups at position 2, relatively close to the side-chain nitrogen atoms. Loxapine, an effective antipsychotic, blocks D2-type receptors and has side effects similar to those reported for the phenothiazines. Its metabolism involves aromatic hydroxylation to give several phenolic metabolites that have higher affinity for D2 receptors than the parent. It is also N-demethylated to yield amoxapine (an antidepressant drug), which inhibits norepinephrine (NE) neurotransporter to block neuronal NE reuptake.

Clozapine. The dibenzodiazepine derivative is clozapine (Clozaril). It is not a potent antipsychotic on a milligram basis (note the orientation of the N-methyl piperazino group relative to the chlorine atom). In addition to their moderate potencies at DA receptors (mainly D4), clozapine interact with varying affinities at several other classes of receptors (a1 and a2 adrenergic, 5-HT1A, 5-HT2A, 5-HT2C, muscarinic cholinergic, histamine H1, and others). It is effective against both positive and negative symptoms of schizophrenia and has a low tendency to produce EPS. Clozapine has proved effective even in chronically ill patients who respond poorly to standard neuroleptics. However, there are legal restrictions on its use because of a relatively high frequency of agranulocytosis. As a rule, two other antipsychotics are tried before recourse to therapy with clozapine. Clozapine is metabolized

preferentially by CYP3A4 into demethylated, hydroxylated, and N-oxide derivatives that are excreted in urine and feces. Elimination half-life averages about 12 hours. Other cloza-pine-like atypical antipsychotics may lack a 2-Cl substituent on the aromatic ring (e.g., olanzapine and quetiapine).

Olanzapine and Quetiapine. Clozapine analogs, olanzapine (Zyprexa) and quetiapine (Seroquel) possess tricyclic systems with greater electron density than chlorpromazine. The drugs are atypical antipsychotics. Olanzapine is a more potent antagonist at D2 and 5-HT2A receptors than clozapine and is well absorbed, but about 40% of an oral dose is metabolized before reaching the systemic circulation. Plasma concentrations of olanzapine peak at about 6 hours after oral administration, and its elimination half-life ranges from 20 to 54 hours. Major readily excreted metabolites of olanzapine are the inactive 10-N-glucuronide and 4'-nor derivatives, formed mainly by the action of CYP1A2, with CYP2D6 as a minor alternative pathway. It may have even lower risk than risperidone and has achieved widespread use.

Overall, these two compounds should bind less strongly to D2 receptors and permit more receptor selectivity among receptor subtypes than typical antipsychotics. This could

Sar OlanzapineSar OlanzapineButyroph None
Figure 12.7

X = F or och3 General structure and SAR of fluorobutyrophenones.

account for decreased striatal Deblocking activity (EPS). Quetiapine is highly metabolized by hepatic CYP3A4 to inactive and readily excreted sulfoxide and acidic derivatives.


The fluorobutyrophenones belong to a much-studied group of compounds, many of which possess high antipsychotic activity. The structural requirements for antipsychotic activity in the group are well worked out.32 General structure and SAR are expressed in the following structure (Fig. 12.7).

Attachment of a tertiary amino group to the fourth carbon of the butyrophenone skeleton is essential for neuroleptic activity; lengthening, shortening, or branching of the three-carbon propyl chain decreases neuroleptic potency. This aliphatic amino nitrogen is required, and highest activity is seen when it is incorporated into a cyclic form. A p-fluoro substituent aids activity. The C=O group gives optimal activity, although other groups, C(H)OH and C(H)aryl, also give good activity. The Y group can vary and assist activity, and an example is the hydroxyl group of haloperidol.

The empirical SARs could be construed to suggest that the 4-aryl piperidino moiety is superimposable on the

2-phenylethylamino moiety of DA and, accordingly, could promote affinity for D2 and D3 receptors. The long N-alkyl substituent could help promote receptor affinity and produce receptor antagonism activity and/or inverse agonism.

Some members of the class are D2 and D3 receptor antagonists and are extremely potent antipsychotic agents. EPS are extremely marked in some members of this class, which may, in part, be because of a potent DA block in the striatum and almost no compensatory striatal anti-cholinergic block. Most of the compounds do not have the structural features associated with effective anticholinergic activity.

Haloperidol, USP. Haloperidol, 4[4-(p-chlorophenyl)-4-hydroxypiperidone]-4'-n-fluorobutyrophenone (Haldol), the representative of several related classes of aromatic butylpiperidine derivatives, is a potent antipsychotic useful in schizophrenia and in psychoses associated with brain damage. It is frequently chosen as the agent to terminate mania and often used in therapy for Gilles de la Tourette syndrome. Haloperidol-induced dyskinesias may involve neurotoxicological metabolite similar to dopaminergic toxicant MPP+ (Fig. 12.8).

Haloperidol Metabolism
Figure 12.8 • Metabolism of haloperidol and its possible neurotoxic metabolites.
Damaged Brain From Taking Haloperidol

Droperidol, USP. Droperidol, 1-{1-[3-(^-fluoroben-zoyl)propyl] -1,2, 3,6-tetrahydro-4-pyridyl} -2-benzimida-zolinone (Inapsine), may be used alone as a preanesthetic neuroleptic or as an antiemetic. Because of its very short-acting and highly sedating properties, its most frequent use is in combination (Innovar) with the narcotic agent fentanyl (Sublimaze) preanesthetically.

Risperidone. Risperidone (Risperdal, a benzisoxazole) has the structural features of a hybrid molecule between a butyrophenone antipsychotic and a trazodone-like antidepressant. Its superior side effects profile (compared with haloperidol) at dosage of 6 mg/d or less and the lower risk of tardive dyskinesia have contributed to its very widespread use. It benefited refractory psychotic patients, with parkinsonism controlled at one tenth the dose of antiparkinsonian drugs used with haloperidol.33 Coexisting anxiety and depressive syndromes were also lessened. It is reported to decrease the negative (e.g., withdrawal, apathy) as well as the positive (e.g., delusions, hallucinations) symptoms of schizophrenia. This is reportedly a consequence of the compound's combination 5-HT2-D2 receptor antagonistic properties.34 Overall, the reasons for the decreased EPS and effectiveness against negative symptom are still under investigation. It is an important atypical antipsychotic. Risperidone is metabolized in the liver by CYP2D6 to an active metabolite, 9-hydroxyrisperidone. Because this metabolite and risperidone are nearly equipotent, the clinical efficacy of the drug reflects both compounds.

Risperdal MetabolitesRisperidone Pathways

an active metabolite Figure 12.9 • Major metabolic pathway of ziprasidone.

Metabolic Pathways Famous
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