Neuroleptic analogs

Fig. 37.3. Principal components biplot showing the positions of 6 substituted oxazepine (O) and 6 substituted thiazepine (S) neuroleptics with respect to three physicochemical parameters and two biological activities [41,43]. The data are shown in Table 37.6. The thiazepine analogs are represented by means of filled symbols. The horizontal and vertical components represent 50 and 39%, respectively, of the variance in the data.

To search for novel neuroleptic agents, attention has been given to structural modifications of dibenzoepines such as clozapine (9) [ 17] as a clinically active atypical antipsychotic, and its analogous fluperlapine (10) [18, 19] with a pharmacological resemblance to clozapine. Some 2-piperazinyl-5-phenyl-... 

Mesoridazine acts analogous to other phenothiazine neuroleptics and is used for schizophrenia, behavioral problems, psychoneurotic displays, and in severe and chronic alcoholism. Synonyms of this drug are lidanil, serentil, and others. 

Some neuroleptic agents, like cycloindole (497), which has a modified tryptamine structure, and flucindole (498), a difluoro analog of cycloindole, have found use in therapy because of their anti-depressant and anti-psychotic activity (463,464) (Scheme 4.11). 3-Chlorocarbazole (385) (see Scheme 2.102), isolated from female bovine urine, has Diazepam-like activity (354). 

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. 

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.

In one patient who took 900 mg of phenelzine, there was a marked excess of nrinary and plasma catecholamines, analogous to pheochromocjdoma, and the patient was successfully managed with alpha-adrenoceptor antagonists (44). In another patient, who probably took about 2000 mg of phenelzine, hyperpyrexia was prominent and responded to dantrolene sodium (45). The authors noted clinical similarities to malignant hyperpyrexia and neuroleptic malignant syndrome. 

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... 

Table 26.5 shows some experimental data for the active isomers of the fluoro analogs of the tricyclic neuroleptic clotepin as compared to the corresponding racemate. In this example, it appears clearly that the nenroleptic activity is concentrated in the dextrorotatory componnd (+)2 whereas the toxicity resides in the (-)3 antipode. 

It has been possible to produce a balanced type of anesthesia wherein low-potency N20 is combined with an opioid analgesic, usually the meperidine analog fentanyl (Fig. 5-10), or the more recent analogs sufentanil and alfentanil. When a butyrophenone-type neuroleptic (see later), particularly droperidol, is added, a state of neuroleptoanesthesia is produced where, without loss of consciousness, analgesia sufficient for surgery is achieved during which the patient still responds to commands.6... 

All these effects have an important, hitherto mostly neglected influence on drug activity [214]. The differences in inhibitory activities of trimethoprim (TMP) analogs in cell-free and whole cell systems of Escherichia coli strains being sensitive and resistant to TMP, the interaction of amphiphilic benzylamines with artificial bilayers, the interaction of neuroleptics with bilayer membranes (measured by NMR techniques), and the reversal of multidrug resistance by amphiphilic agents could quantitatively be described in relation to these effects [214]. 

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