Haloperidol structure

Chlorpromazine is technically described as a phenothiazine, as are thioridazine and fluphenazine. Together with their structural analogues the thioxanthenes (e.g., clopenthixol) and the butyrophenones (e.g., haloperidol), the phenothiazines comprise the three major families of typical neuroleptics. They were developed in the late 1950s and early 1960s (Table 11.3). All these drugs block dopamine receptors, principally the D2 subtypes, with an affinity that correlates highly (r = +0.90) with their clinical... 

FIGURE 4.13 Structures of the CYP2D6 substrates, amitriptyline, codeine, haloperidol, and propranolol, and their metabolites. 

DA receptors are classified as D1 to D5. Bromocriptine and pergolide act as agonists at certain subtypes, and neuroleptics such as haloperidol and thorazine act as antagonists. It is produced by several nuclei in the brain, but most notably the substantia nigra and the ventral tegmental area (VTA) of the midbrain. The substantia nigra mainly projects to the basal ganglia and the VTA supplies limbic and cortical structures. 

Because of multiple receptor actions, which occur at different concentrations, different neuroleptics have different action profiles. There are many classifications for neuroleptic drugs, the least useful of which is probably based on their chemical structure. Other classifications include linear classifications based on the propensity to cause EPS, or multidimensional ones such as the Liege star which combines information on three positive effects (anti-autistic, antiproductive, antipsychotic), and three negative (hypotensive, extrapyramidal, sedative). In a general way, the more sedative neuroleptics such as levomepromazine, used more to treat acute agitation states, cause more hypotension related to alpha blockade, whereas those that act best on delirium (productive states) such as haloperidol tend to cause more EPS. 

Butyrophenones are a very old family of nonspecific antagonists of dopamine. Nevertheless, haloperidol and its close analogues melperone, bromperidol, trifluperidol) are still marketed. Timiperone, biriperone, benperidol, droperidol, fluanisone, and pipamperone have more structural changes in the piperidine moiety (Figure 8.28). 

The first agent of this class to be introduced in the clinic, haloperidol (18-8), interestingly shares the 4-phenylpiperidine structural fragment found in the central analgesic agent meperidine and its derivatives (see Chapter 7). The former compound may well have been discovered in the course of further SAR studies on the opiate [20]. An unusual synthesis of haloperidol starts with the product (18-1) from Friedel-Crafts acylation of 4-fluorobenzene with succinic anhydride. Successive protection of the... 

FIGURE 11 — 14. Structural formula of haloperidol, one of the most widely prescribed conventional antipsychotic drugs during the height of the conventional antipsychotic era, prior to the mid-1990s. 

During the course of a study of the salts formed by saccharin with quinine, haloperidol, mirtazapine, pseudoephedrine, lamivudine, risperidone, sertraline, venlafaxine, zolpidem, and amlodipine, a 1 1 cocrystal of saccharin and piroxicam was detected [68]. In the crystal structure, the asymmetric unit was found to consist of one saccharin molecule and one zwitterionic piroxicam molecule that were linked by two sets of N—H O hydrogen bonds. The piroxicam-saccharin synthons were in turn linked through bridging C—H O hydrogen bonds. Interestingly, the drug substance solubility out of the cocrystal was found to be comparable to that of the marketed piroxicam product. 

Fig. 17. Similar structural feature among six structurally diverse antipsycotropics (molindone, Chloropromazine, chlorptothixine, haloperidol, pimozide and sulpiride)...

Rothblat DS, Schneider JS (1997) Regionally specific effects of haloperidol and clozapine on dopamine reuptake in the striatum. Neurosci Lett 228 119-22 Roy-Byrne PP (2005) The GABA-benzodiazepine receptor complex structure, function, and role in anxiety. J Clin Psychiatry 66 Suppl 2 14-20... 

In recent years traditional neuroleptics, as exemplified by chlorpromazine, have been structurally modified to produce drugs with greater affinity for dopamine receptors while retaining some of their activity on other receptor systems (e.g. on alpha] adrenoceptors, 5-HT2 receptors and histamine] receptors). In the non-phenothiazine series, a high degree of specificity for the D2 receptors has been achieved with sulpiride and pimozide, with haloperidol showing antagonistic effects on the 5-HT2 and alpha] adrenoceptors in addition to its selectivity for D2 receptors. The czs-(Z) isomers of the thioxanthines are potent neuroleptics that, in addition to... 

The butyrophenones and diphenylbutylpiperidines differ from the phenothia-zines and thioxanthines in that they are not tricyclic structures. The first butyrophenone to be developed was haloperidol, and this is the most widely used, potent neuroleptic. Unlike many of the phenothiazines, these neuroleptics largely lack antihistaminic, anticholinergic and adrenolytic activity they are also non-sedative in therapeutic doses. Their potent antidopaminergic activity renders them likely to cause extrapyramidal side effects. Of the various butyrophenones shown in Figure 11.10, benperidol has been selectively used to suppress asocial sexual behaviour. 

Fig. 3.1 Morphine 1 has been the lead structure for the development of the major analgesic fentanyl 2, the antitussive drug dextromethorphan 3, the constipating drug loperamide 4, and the neuroleptic drug haloperidol 5.

Fig. 13.1 Chemical structure of clozapine, some of its structural analogues, typical (chlorpromazine, haloperidol) and atypical antipsychotics (risperidone, ziprasidone, sertindole and amisulpride) unrelated to clozapine.

Butyrophenones, such as haloperidol and droperidol, have a different structure but are clinically similar to the thioxanthenes. They are potent dopamine... 

Figure 2.3 Dextromethorphan 6, the unnatural enantiomer of a narcotic morphine analog, is an antitussive drug. The antidiarrhea drug loperamide 7 and the neuroleptic drug haloperidol 8 also resulted from structural modification of morphine. The morphine antagonist nalorphine 9 differs from the opioid agonist morphine 3 (Figure 2.2) only by having an N-allyl group instead of the N-methyl group.

An example may help to clarify this statement Figure 13.4 shows the 10 highest-ranking compounds that were retrieved from the COBRA database by a topological pharmacophore similarity search (CATS method, see below). The query structure was Haloperidol, a dopamine (D2) receptor antagonist. Not surprisingly classic variations of the query structure are found in ranks 1 and 2. These are not very... 

Figure 13.4 Results of a CATS similarity search. Similarity between the query structure (Haloperidol, a D2 antagonist upper left) and database compounds was defined in terms of a topological pharmacophore descriptor. The top 10 most-similar molecules found are shown.

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