4- Neuroleptics

Neuroleptic drugs are used in the treatment of psychosis, such as schizophrenia they are generally antagonist ligands of dopamine at the central nervous system level. Indications and therapeutic effects of the various families of neuroleptics result from two factors. The first one is the specifity of the ligand toward the different types of dopaminergic receptors, which are unequally distributed in the 

Risperidone is a selective antagonist of both D2 and 5-HT2 receptors. It is currently the neuroleptic leader in the treatment of schizophrenia and of dementia. 

Penfluridol (Johnson Johnson) 1973 Pimozide (Johnson Johnson) 1971 

A 5-HTi agonist, oxaflozane, originally marketed for depressive disorders, has been abandoned. 

Nemifitide, apentapeptide, is in Phase II/III clinical trials for the treatment of major depression. 

After neuroleptic treatment of a psychotic episode is initiated, the antipsychotic effect proper manifests following a latent period. Acutely, psychomotor damping with an-xiolysis and distancing is noted. Tormenting paranoid ideas and hallucinations lose their subjective importance (A, dimming of flashy colors) initially, however, the psychotic process persists but then wanes gradually over the course of several weeks. 

Complete normalization often cannot be achieved. Even though a cure is unrealizable, these changes signify success because (a) the patient obtains relief from the torment of psychotic personality changes (b) care of the patient is facilitated and (c) return into a familiar community environment is accelerated. Neuroleptic therapy utilizes different drug classes, namely phenothiazines, butyro-phenones, and the atypical neuroleptics. 

Neuroleptics do not have anticonvulsant activity. Because they inhibit the thermoregulatory center, neuroleptics can be employed for controlled hypothermia ( artificial hibernation ). 

Chronic use of neuroleptics can on occasion give rise to hepatic damage associated with cholestasis. A very rare, but dramatic, adverse effect is the malignant neuroleptic syndrome (skeletal muscle rigidity, hyperthermia, stupor), which can have a fatal outcome in the absence of intensive countermeasures (including treatment with dantrolene). 

With other phenothiazines (e.g., fluphen-azine with a piperazine side chain substituent), antagonism at other receptor types tends to recede into the background vis-a-vis the blockade of D2 dopamine receptors. In panel (B) on p. 235 the D2 receptor af nity of the drugs concerned is defined as ++, while the differences in absolute af nity for the other receptors are ignored. 

Ergoline [I], Single or double bond at 8 or 9 but no cumulative double bond. 

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In addition to halopeiidol, the putative neuroleptics, limcazole (311), lemoxipiide (312), and gevotioline (313) bind to (7-ieceptois as does the dopamine uptake blocker, GBR 12909 (314) and two ligands active at the NMDA receptor, ifenprodil (315) and CNS 1102 (316). NPC 16377, (317) is a selective (7-teceptor ligand. MAO inhibitors and antidepressants also bind to (7-teceptors. Some evidence indicates that (7-teceptors in the brain are in fact a form of cytochrome which may account for the diversity of ligands interacting with (7-sites. 

Neuroleptic analgesia is so called because the combination of a major tranquilizer, a neuroleptic dmg, and a potent opiate produces an anesthetic state characterized by sedation, apathy, and mental detachment (see Psychopharmacological agents) (152). Iimovar [8067-59-2] a combination of droperidol [648-72-2], C22H22FN2O2, (19) and fentanyl (9) citrate, is used for procedures that do not require muscle relaxation. However, the onset of action is slow. 

Schizophrenia is perhaps the most debiUtating psychiatric illness in modem medicine, affecting about 1% of the general population. Many of those affected require institutionalization (180). Unfortunately, the compounds available to treat this disorder are not hiUy effective in treating the spectmm of symptoms in all patients. Adverse effects are also a problem (181). In addition, available antipsychotic (neuroleptic) dmgs (Table 5) can at most only provide symptomatic rehef. 

I-Methyl-4-[3(5)-pyrazolyl]quinolinium iodides (688) also failed to depress blood sugar levels significantly (69JMC1124). Neuroleptic-like effects of some /3-aminoketones (689) containing a pyrazole nucleus have been described in the literature (B-80MI40406). The... 

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

To anticipate briefly, shortening the length of the side chain in the phenothiazines from three to two carbon atoms changes I he activity of the products from neuroleptics to antihistaminic iigents. A rather similar effect is seen in the tricyclic antidepressants. Reaction of ketone, 27, with the Grignard reagent I rom 4-chloro-l-methylpipyridine (35) affords the tertiary alco-liol, 36. Dehydration gives the antihistamine, cyproheptadine (37). ... 

The most prominent pharmacologic activity exhibited by phenothiazines bearing the 1,3-propyldiamine side chain is, of course, that of a neuroleptic agent. Treatment of psychoses and severe neuroses constitutes the largest single use of these so-called... 

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. ... 

An interesting additional example of the interchangeability of the bridging atoms in the neuroleptic series comes from the finding that the biologic activity of the phenothiazines is maintained in a compound that contains an extra atom on the nitrogen... 

Alkylation of the intermediate, 41, with l-bromo-3-chloro-ethane affords 49, the use of this to alkylate iv-(2-hydroxyethyl) piperazine affords oxypendyl (50), a neuroleptic with good antiemetic and antivertigo properties. 

Major tranquilizer. A drug useful in the control of schizophrenia. Also referred to as neuroleptic or antipsychotic. 

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. 

Typical antipsychotic drugs Neuroleptic dtugs conventional antipsychotic diugs older antipsychotic diugs ... 

The antipsychotic activity of neuroleptics (D2-like receptor antagonists) has led to the development of many different ligands for the D2 receptor. These drugs... 

Dyskinesias are abnormal movements, usually caused by neurological diseases or by diugs used to treat neurological (e.g., levodopa) or psychiatric diseases (e.g., neuroleptics). 

Neuroleptic-like malignant syndrome is a serious but very rare adverse effect of some drugs, of e.g., neuroleptics, some anaesthetics and apparently tolca-pone. Symptoms include hyperthermia, muscle deterioration, even dissolution. 

Neuroleptics or antipsychotics suppress the positive symptoms of schizophrenia such as combativeness, hallucinations and formal thought disorder. Some also alleviate the negative symptoms such as affective blunting, withdrawal and seclusiveness. Neuroleptics also produce a state of apathy and emotional indifference. Most neuroleptics block dopamine D2-receptors but some, like clozapine, also block dopamine D4-receptors or serotonin 5-hydroxytryptamine2A-receptors. 

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