Neuroleptics butyrophenones

The numerous neuroleptic (butyrophenones and diphenylbutylamines) are classical examples of this strategy (cf. Chapter 8)." °... 

Nakalsuka, 1., Kawahara. K., and Yo.shilake, A., Labeling of neuroleptic butyrophenones. in. Synthesis of 2 -amino-4 -nuoro-4(4-hy-droxy-4(3-trifluoromcthylphcnyl)piperidino-2- C]butyrophenone, J. Labelled Compd. Radiopharm.. 18, 495, 1981 Chem. Abstr., 95, 97533, 1981. 

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

The role of fluonne in the development of CNS agents has been reviewed [14] Ruonnated phenothiazines, typified by fluphenazine (7[Pg.1121]

But (i) Effect only antagonised by some neuroleptics, phenothiazines-YES thioxanthenes-YES butyrophenones-NO (metoclopromide inactive)... 

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... 

Butyrophenones A family of typical antipsychotic drugs (neuroleptics), the most commonly used being haloperidol. 

Whatever the underlying causes may be, neuroleptic medications are the most effective treatment for schizophrenia. All antipsychotic medications have some form of dopamine receptor antagonism and they are distinguished by their chemical class. The phenothiazines include chlorpromazine (Thorazine), thioridazine (Mellaril), mesoridazine (Serentil), trifluoperazine (Stelazine), fluphenazine (Prolixin), and prochlorperazine (Compazine). The thioxanthenes include chlorprohixine (Taractan) and thiothixene (Navane). Butyrophenones are represented by haloperidol (Haldol). Loxapine (Loxitane) is a dibenzoxapine, and molindone (Moban) is a dihydroindolone. 

Two types of dopamine receptors have been characterized in the mammalian brain, termed and D2. This subtyping largely arose in response to the finding that while all types of clinically useful neuroleptics inhibit dopaminergic transmission in the brain, there is a poor correlation between reduction in adenylate cyclase activity, believed to be the second messenger linked to dopamine receptors, and the clinical potency of the drugs. This was particularly true for the butyrophenone series (e.g. haloperidol) which are known to be potent neuroleptics and yet are relatively poor at inhibiting adenylate cyclase. 

Detailed studies of the binding of H-labelled haloperidol to neuronal membranes showed that there was a much better correlation between the therapeutic potency of a neuroleptic and its ability to displace this ligand from the nerve membrane. This led to the discovery of two types of dopamine receptor that are both linked to adenylate cyclase but whereas the Di receptor is positively linked to the cyclase, the D2 receptor is negatively linked. It was also shown that the receptor is approximately 15 times more sensitive to the action of dopamine than the D2 receptor conversely, the receptor has a low affinity for the butyrophenone and atypical neuroleptics such as clozapine, whereas the D2 receptor appears to have a high affinity for most therapeutically active neuroleptics. 

Neuroleptic activity profiles. The marked differences in action spectra of the phenothiazines, their derivatives and analogues, which may partially resemble those of butyrophenones, are important in determining therapeutic uses of neuroleptics. Relevant parameters include antipsychotic efficacy (symbolized by the arrow) the extent of sedation and the ability to induce ex-trapyramidal adverse effects. The latter depends on relative differences in antagonism towards dopamine and acetylcholine, respectively (p. 188). Thus, the butyrophenones carry an increased risk of adverse motor reactions because Lullmann, Color Atlas of Pharmacology 2000 Thieme All rights reserved. Usage subject to terms and oonditlons of lloense. 

It also seems plausible that antipsychotic drugs competitively bind with dopamine receptors and block the action of dopamine on corresponding receptor sites, thus lowering psychotic activity. Central dopamine receptors are subdivided into Dj, D2, and according to some sources, Dj receptors. These receptors have a high affinity for dopamine, but they differ in sensitivity to neuroleptics of various chemical classes. For example, drugs of the phenothiazine series are nonselective competitive Dj and D2 antagonists. Unlike phenoth-iazines, antipsychotics of the butyrophenone series such as haloperidol display selective action only on D2 receptors. 

A number of different compounds of the piperidine and piperazine series with p-fluorobuty-rophenone group substitutions at the nitrogen atom display significant neuroleptic activity (haloperidol, trifluperidol, droperidol, methorin). There is a considerable interest in butyrophenone derivatives as antipsychotic agents as well as in anesthesiology. They exhibit pharmacological effects and a mechanism of action very similar to that of phenothiazines and thioxanthenes in that they block dopaminergic receptors. However, they are more selective with respect to D2 receptors. 

A. Katsifis, K. Hamacher, J. Schnitter, G. Stdcklin, Optimization studies concerning the direct nucleophilic fluorination of butyrophenone neuroleptics, Appl. Radiat. Isot. 44 (1993) 1015-1020. 

K. Hamacher, W. Hamkens, Remote-controlled one-step production of F-18 labeled butyrophenone neuroleptics exemplified by the synthesis of nca [F-18]N-methylspi-perone, Appl. Radiat. Isot. 46 (1995) 911-916. 

C. Shiue, J.S. Fowler, A.P. Wolf, M. Watanabe, C.D. Arnett, Synthesis and specific activity determination of NCA F-labeled butyrophenone neuroleptics Benperidol, haloperidol, spiroperidol and pipamperone, J. Nucl. Med. 26 (1985) 181-186. 

The pharmacology of all these neuroleptics is extremely complex. Briefly, phenoth-iazines and related drugs have a calming effect on psychotic patients, without producing excessive sedation. Other central effects include the important antiemetic effect in disease-, drug-, or radiation-induced nausea, but not so much in motion sickness. Butyrophenones are more effective antiemetics than phenothiazines and also potentiate the activity of anesthetics. 

Lengthening of the N-substituent in meperidine leads to active analgesics such as the propiophenone analog, which is 200 times more active than meperidine. However, the butyrophenone derivative suddenly becomes a highly active neuroleptic without any analgesic activity. 

The choreiform movements and behaviors can be only partially controlled by phenothiazines or butyrophenone neuroleptics. 

Haloperidol (156) and similar butyrophenone derivatives, e.g. droperidol (123), are neuroleptics that were developed from the pethidine series of analgesics. Some (3-aminoketones (Mannich bases) also have neuroleptic activity, an example being molindone (157). 

The synthesis of fluorine-18-labelled receptor-based radiopharmaceuticals carried out before 1986 have been reviewed331 and the methods applied for the synthesis of 18F-butyrophenone neuroleptics such as spiroperidol (spiperone), haloperidol have been critically evaluated. The synthesis for preparing 7V-(2-[18F]fluoroethyl)spiperone330 involving the [18F]fluoride ion displacement of a suitable leaving group on the ethyl side chain was found to be particularly good (>50% yield). 

Antipsychotic drugs include the older phenothiazines and butyrophenones, as well as newer atypical drugs. All of these can cause CNS depression, seizures, and hypotension. Some can cause QT prolongation. The potent dopamine D2 blockers are also associated with parkinsonian-like movement disorders (dystonic reactions) and in rare cases with the neuroleptic malignant syndrome, characterized by "lead-pipe" rigidity, hyperthermia, and autonomic instability (see Chapter 29 Antipsychotic Agents Lithium). 

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. 

The diphenylbutylpiperidines are structurally related to the butyrophenones and have essentially similar properties. Pimozide is the most well-established member of this series and is a potent neuroleptic that, like other potent neuroleptics, is likely to cause extrapyramidal side effects. 

Figure 11.10. Chemical structure of the butyrophenone and diphenylbutylpiper-idine series of neuroleptics indicates that N has been replaced by C.

In CONCLUSION, the use of the "classical" neuroleptics, as exemplified by the phenothiazines, thioxanthines, butyrophenones and diphenylbutyl-piperidines, has been a landmark in the pharmacotherapy of schizophrenia and psychotic disorders. The efficacy of such drugs in the alleviation of the symptoms of schizophrenia is universally accepted. However, it is also evident that they have a spectrum of adverse effects that frequently renders their long-term use problematic. Side effects such as akathisia, Parkinsonism, tardive dyskinesia and the all too frequent changes in peripheral autonomic activity are largely predictable from the structure of the molecules and the basic animal pharmacology data. Such adverse effects, and the difficulties encountered when attempting to reduce their frequency and severity by concurrent medication, has stimulated the development of "atypical" neuroleptics such as clozapine and risperidone which, hopefully, will combine efficacy with a reduction in side effects. 

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