4- piperidin Haloperidol

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. 

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). 

Haloperidol (55) Haldol McNeil Butyrophenone (piperidine) 2 1-15 PO, IM (lactate)... 

An initial strategy to optimize the drugabil-ity of (2) focused on two fragments with potential liabilities. The 4-hydroxy phenyl piperidine is also present in haloperidol and implicated with neurotoxicity, and the tricyclic dibenzothiepine is a common feature of CNS-active drugs. As indicated in Table 4.2, removal of the 4 -hydroxy led to a complete loss of potency against CCRl. 

The authors also point out that there may be a limited set of amino acid residues that are capable of binding a given chemical feature, such as haloperidol s fluorophenone moiety or piperidine nitrogen. The antibody residues selected in response to these groupings therefore suggest possible receptor binding site residues. 

Modification of the haloperidol butyrophenone side chain by replacement of the keto function with a di-4-flurophenylmethane moiety results in diphenylbutyl piperidine neuroleptics, such as pimozide, penfluridol, and fluspirilene. The diphenylbutyl piperidines neuroleptics have a longer duration of action than the butyrophenone analogues. All are effective in the control of ... 

C. Loperamide is a synthetic piperidine derivative structurally similar to diphenoxylate and haloperidol. It may produce opioid-like toxicity In overdose. 

The piperidine and side chain motif have been retained but both fluorophenyl groups have been replaced with a 1,2-benzisoxazole group. Haloperidol is a strong DA D2-receptor antagonist that lacks significant serotonergic activity. It is a representative of the butyrophenone class of antipsychotics. Inspection of the risperidone structure... 

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