Neuroleptic activity

The efficacy of the phenothiazines for the treatment of various psychoses led to extensive synthetic programs aimed at modulation of the biologic spectrum of these molecules. As seen elsewhere, much of this work has centered on changes of the nature of the atoms that constitute the center ring. Thus, for example, it has proven possible to replace the nitrogen atom of the phenothiazine by carbon while maintaining neuroleptic activity. 

Reduction of the exocyclic double bond generally decreases neuroleptic activity in this series. Some of these compounds, however, show other activities. Methixene (44), for example, is used as an antispasmodic agent. It is prepared by alkylation of the sodium salt of thioxanthene (43) with w-methyl-3-chloromethyl-piperidine. ... 

The benzazepines are not as important pharmacologically as their more famous relatives the benzodiazepines. However, 3-aryl-2-(piperazin-l-yl)-5//-l-benzazepines, e.g. 14, and 17/-3-benzazepin-2-amines 15 possess neuroleptic activity,60 and antihypertensive activity,45 61 respectively. 

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. 

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. 

Tardive dyskinesia Tardive dyskinesia, a syndrome consisting of potentially irreversible, involuntary, dyskinetic movements may develop in patients treated with neuroleptics (eg, antipsychotics). Amoxapine is not an antipsychotic, but it has substantive neuroleptic activity. 

The neuroleptic activity of 10,11 -dihydrodibenzo[6,/]thiepins has led to the synthesis of a very large number of derivatives. Protiva and coworkers have been responsible for a large proportion of work in this area and have published over one hundred papers in this series (81CCC1199). 

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). 

Phenothiazine derivatives have found many applications in todays chemical industry they have been and are used primarily as dyestuffs, antioxidants and in pharmaceutical preparations. This application is due to the discovery of their neuroleptic activity (1 ) (e.g. Chlorpromazine), but allergic skin reactions and ocular opacity are known to occur during therapy. 

Kabanov, A.V., et al. 1989. The neuroleptic activity of haloperidol increases after its solubilization in surfactant micelles. Micelles as microcontainers for drug targeting. FEBS Lett 258 343. 

Thioxanthenes differ from the phenothiazines by having a carbon atom instead of a nitrogen atom in the central ring. The thioxanthenes can be represented as two geometric stereo-isomers Cis(Z)- and trans(E)- compounds. Only the cis Z)- compounds have been shown to be neuroleptically active [83]. 

Kabanov AV, Chekhonin VP, Alakhov VY, Batrakova EV, Lebedev AS, Melik-Nubarov NS, Arzhakov SA, Levashov AV, Morozov GV, Severin ES, Kabanov VA (1989c) The neuroleptic activ-... 

The tricyclic antipsychotics may be dissected into three substructures (Fig. 10.1), those being the pendent amine functionality (Site A), the diaryl heterotricyclic (Site C), and the intervening alkyl chain (Site B) (295). When considering the effect of structure on neuroleptic activity, it is informative to examine each of the three substructures of the tricyclic-in isolation to see how individual changes within each of these regions impacts the pharmacological properties of the resultant compound. 

The distance between Sites A and C is critical for neuroleptic activity, with a three carbon chain being optimal. Shortening the chain to two carbons has the effect of amplifying the anticholinergic and antihistaminic properties. The amino ethyl derivatives diethazine (2) has proven useful in the treatment of Parkinson s disease, while promethazine (3)is effective as an antihistamine. 

Analy sisofthehuman metabolites of remox-ipride identified two products resulting from demethylation (332). The 3-bromo-6-methoxy salicylamide (77) (FLA 797) showed a much greater affinity for the D2 receptor than did either its isomer (FLA 908) (78) or the parent compound. This result lead to speculation that the neuroleptic activity of remoxipride was caused by this metabolite. 

Antipsychotic Agents - In acute schizophrenia patients, the potent, long-lasting tranquilizer, AL 1965 (23) showed neuroleptic activity and a high incidence of extrapyramidal side effects (EPS).3°... 

A series of novel neuroleptic agents derived from alpha-tetralone and N-arylpiperazine has been prepared. 38 Moderate activity in inhibiting amphetamine hypermobility and in producing hypothermia was found, with compound (26) being the most active. Another N-arylpiperazine analog (27) also had neuroleptic activity in antagonizing amphetamine and apomorphine stereotypy and production of catalepsy. 39... 

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