Butyrophenone antagonists

Butyrophenones Butyrylcholinesterase C2 Domain C Kinase C-reactive Protein Ca2+-ATPase Ca2+-binding Proteins Ca2+ Channel Ca2+ Channel Antagonists Ca2+ Channel Blockers... 

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. 

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). 

Chlorpromazine Prochlorperazine Fluphenazine Butyrophenones Droperidol Domperidone Antihistamines Promethazine Diphenhydramine Benzamides Metoclopramide Serotonin antagonists Ondansetron Granisetron Tropisetron... 

The differential clinical actions of DA blockers on the DA receptor subtypes have not been defined with precision. Most neuroleptics appear to act at both D-1 and D-2 receptors. Some differences exist, however. The thioxanthenes bind to sites related to both DA receptor subtypes, but the butyrophenones seem to prefer sites assocaited with D-2 receptors, binding only weakly to those identified with D-1 receptors. Sulpiride, molindone and metoclopramide are relatively selective D-2 antagonists. 

In our model, we have indicated that atypical antipsychotics (12) (sulpiride, metoclopramide, molindone, and Ro 22-1319) differ from classical neuroleptics (tricyclics, butyrophenones, butaclamol, diphenyl-piperidines) by lacking a lipophilic functional group on the basic nitrogen that could extend into the auxiliary binding site identified in our model. The absence of this lipophilic functionality may now be stated to be the characteristic which distinguishes selective D-2 dopamine receptor antagonists from non-selective antagonists. 

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

Postoperative vomiting is related to the duration of anaesthesia and has many causes. Metoclopramide, a 5-HTj receptor antagonist, e.g. ondansetron or a butyrophenone, e.g. haloperidol or droperidol, may be used. The condition affects some 30% of patients... 

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. 

Binding studies with tritiated neuroleptics have established the existence of two types of central DA receptors D[ and D2 their numbers and ratios vary in brain areas. Most interesting, however, is that both are altered in drug-naive schizophrenics. Emphasis has concentrated on the D2 subtype that seems implicated in the observable clinical responses. The role of the postsynaptic Dt receptor is not clear. It is known, however, that even though neuroleptic drugs are D,/D2 antagonists, in vitro D2 effects are achieved at 103 lower concentrations. D2 receptors are also located in central areas outside the BBB. One is the CTZ in the medulla. Presynaptic stimulation, which leads to DA inhibition there, may be the reason that many of the phenothiazine and butyrophenone neuroleptic drugs also excel as antiemetics (see comments, Table 12-11). It also explains why several DA2... 

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