The pharmacology of penfluridol (R 16341) a new potent and orally long-acting neuroleptic drug

doi:10.1016/0014-2999(70)90043-9

European Journal of Pharmacology

Volume 11, Issue 2, 15 July 1970, Pages 139-154

https://doi.org/10.1016/0014-2999(70)90043-9 Get rights and content

Abstract

R 16341, 4-(4-chloro-a,a,a-trifluoro-m-tolyl)-1[4,4-bis(p-fluorophenyl)butyl]-4-piperidinol is a new member of the potent and long-acting series of diphenylbutyl piperidine neuroleptics of which pimozide is the prototype.

In animals the pharmacological profile of R 16341 resembles that of typical neuroleptic compounds.

R 16341 is very potent by the oral route and has a longer duration of action than any other neuroloptic we have tested.

At 4 times the minimum ED₅₀-value of the anti-apomorphine test in dogs, R 16341 has a duration of action of about 7 days.

The onset of action of R 16341 is gradual and smooth and its peak effect is generally reached 24 to 48 hr after administration. R 16341 is relatively atoxic with a safety margin of 1:1000 in rats and dogs. Qualitatively R 16341 is more closely related to haloperidol and pimozide than to chlorpromazine, the side-effect liability is expected to be lower than that of chlorpromazine, when hypotensive and autonomic side-effects are concerned and to be lower than that of haloperidol when undesirable neurological side-effects are concerned.

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Mosquitocidal activity of penfluridol as juvenile hormone antagonist
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Citation Excerpt :
Penfluridol exhibited a significant mosquitocidal activity against 2nd and 3rd instar larvae of A. albopictus, with 1.3–2.0 times lower LC50 values compared to those of pyriproxyfen. In animals, Penfluridol has been known as a long-acting, oral neuroleptic drug belonging to the diphenylbutylpiperidines (Janssen et al., 1970). The pharmacological profile of penfluridol is a typical antipsychotic and a dopamine receptor blocking agent (Jackson et al., 1975).
Juvenile hormone antagonists (JHANs) are known to interfere with the formation of juvenile hormone (JH) receptor complex. JHANs might be effective for control of target pests in larval stages at which stages high level of endogenous JH titer is maintained. In order to identify novel insecticidal compounds, 2352 compounds were surveyed on their JHAN activities using the yeast-two hybrid system. Among 53 compounds with JHAN activities, penfluridol showed high level of insecticidal activity against larvae of Aedes albopictus. JHAN activity was increased in proportion to the concentration of penfluridol. Larvicidal activity of penfluridol was 1.3–2.0 folds higher than that of pyriproxyfen. These results suggested that penfluridol could be useful for control of mosquito larvae.
Normal and abnormal determinants of dopamine receptor ontogeny in the central nervous system
1984, Progress in Neurobiology
Minireview A systematic study of the pharmacological activities of dopamine antagonists
1979, Life Sciences
The so-called dopamine (DA)-antagonists possess a wide variety of pharmacological activities. The present paper analyses some comparative data that were obtained in the Janssen Research Laboratories, using a large series of DA-antagonists in a representative set of pharmacological tests. This study illustrates the relative importance of the different pharmacological properties of these compounds, provides a tool for further meaningful pharmacological and biochemical research in this area, and discusses the therapeutic potential of these drugs.
Central antiemetic actions of pimozide and haloperidol in the dog
1979, Neuropharmacology
The effect of pimozide and haloperidol against emesis induced by nine agents, whose sites of action in producing vomiting have been clearly demonstrated, were studied in conscious dogs. Pimozide and haloperidol were extremely effective in preventing apomorphine-induced emesis. The 50% protective dose (PD50) of oral and intracerebroventricular (4th ventricle) pimozide against emesis, induced by 0.01mg/kg (threshold dose) of intravenous apomorphine, was 5 μg/kg and 0.3 ng/kg, respectively. The corresponding PD50 for haloperidol was 10 smg/kg orally and 0.3 ng/kg via the 4th ventricle. With an oral dose of 100 μg/kg, pimozide and haloperidol prevented emesis induced by a threshold dose of apomorphine for an average of 6.6 and 4.2 days, respectively. Oral administration of 1 mg/kg of pimozide and haloperidol completely inhibited emesis induced by levodopa or Hydergine. The same dose of either pimozide or haloperidol afforded moderate protection against emesis induced by copper sulfate, but had no effect on emesis induced by Veriloid or pilocarpine. These findings indicate that the primary site of antiemetic actions of pimozide and haloperidol is on the chemoceptive emetic trigger zone in the area postrema of the medulla oblongata. At higher doses, however, depression of the vomiting center in the reticular formation of the medulla may also contribute to their antiemetic activity. Furthermore, pimozide afforded only moderate protection against vomiting induced by morphine while haloperidol was ineffective. Both agents were ineffective against emesis induced by ouabain or acetylstrophanthiclin. Since these latter emetic agents act principally through the trigger zone, this may imply that either the affinity of these agents at the receptor site is different, or these agents act at different receptor sites within the trigger zone.
Neuroleptics and brain self-stimulation behavior
1979, International Review of Neurobiology
Pharmacological studies on self-stimulation and neurochemical identification of the involved pathways gave rise to the catecholamine hypothesis of self-stimulation behavior. According to this hypothesis, the effects of electrical self-stimulation are mediated by noradrenergic and dopaminergic neuronal pathways. However, it is shown that self-stimulation behavior can also be induced by applying electrical stimulation to non-aminergic structures. There are a variety of neuroleptics belonging to different chemical classes—namely, the rauwolfia alkaloids (reserpine-like), the phenothiazines (chlorpromazine-like), the butyrophenones (haloperidol-like), and the diphenylbutylamines (pimozide-like). Particular attention is directed towards neuroleptics that effectively control psychotic symptoms, reduce relapse, and enable patients to be reintegrated into society. The differential inhibition suggests that the neuroleptic inhibitory property depends on the strength of the stimulation. Within a given structure, different response rates are obtained by varying the stimulus parameter combinations (SPCs) and possibly reflect a different rewarding or discriminating level. The neuroleptics are compared based on different pharmacological tests, and appropriate methods make it possible to integrate the self-stimulation test within the results of other pharmacological experiments.
Mechanism of antiemetic action of penfluridol in the dog
1978, European Journal of Pharmacology
In conscious mongrel dogs, the 50% protective dose (PD₅₀) of intracerebroventricular (i.c.v., 4th ventricle) and oral (p.o.) penfluridol against emesis induced by apomorphine 0.01 mg/kg i.v. was 0.7 ng/kg and 1.5 μg/kg, respectively, with a ratio of about 1 to 2,000. Another striking feature of penfluridol as an antiemetic was its long duration of action. With a moderate oral dose, e.g. 10 μg/kg, the protective effect could last several days. Penfluridol, 1 mg/kg p.o., was extremely effective in raising the i.v. threshold emetic dose of apomorphine (1 mg/kg), levodopa (20 mg/kg) or Hydergine (0.09 mg/kg). With such a dose of penfluridol, however, the emetic threshold of oral copper sulfate was not raised. Furthermore, penfluridol had no effect in preventing vomiting induced by Veriloid, peruvoside and pilocarpine. These findings suggest that the primary site of the antiemetic property of penfluridol is a selective action on the chemoceptive emetic trigger zone of the medulla. Penfluridol afforded only moderate protection against vomiting induced by epinephrine, emetine or sodium salicylate, and was not effective against that induced by ouabain, acetylstrophanthidin, morphine, and nicotine. Since these emetic agents act principally through the trigger zone, this may imply that penfluridol administration is not equivalent to surgical ablation of this area. In addition, penfluridol only raised the threshold of emesis induced by apomorphine, levodopa and Hydergine, known to stimulate specifically the dopamine receptors. Furthermore, levodopa at a non-emetic i.v. dose was markedly effective in antagonizing the antiapomorphine action of penfluridol. These results suggest that penfluridol exerts its antiemetic action through an antidopaminergic activity.

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The pharmacology of penfluridol (R 16341) a new potent and orally long-acting neuroleptic drug

Abstract

Maintenance therapy of chronic psychotic patients with a weekly oral dose of R 16341. A controlled and double-blind study

J. Clin. Pharmacol.

The pharmacological estimation of adenosine and histamine in blood

J. Physiol. (London)

A multicentric clinical evaluation of pimozide

Acta Neurol. Psychiat. Belg.

Probit Analysis

Vergleichende pharmakologische Daten uber sechs neue basische 4′-Fluorobutyrophenon Derivate

Arzneimittel-Forsch.

Chemical and pharmacological classification of neuroleptic drugs

On a new series of long-acting antipsychotic drugs: Pimozide, Fluspirilene, R 16341 and related diphenylbutylamines

Chemistry and pharmacology of compounds related to 4-(4-hydroxy-4-phenyl-piperidino)-butyrophenone. Part II. Inhibition of apomorphine vomiting in dogs

Arzneimittel-Forsch.

Chemistry and pharmacology of compounds related to 4-(4-hydroxy-4-phenyl-piperidino)-butyrophenone. Part III. Duration of antiemetic action and oral effectiveness of Haloperidol (R 1625) and of chlorpromazine in dogs

Arzneimittel-Forsch.

Is it possible to predict the clinical effects of neuroleptic drugs (major tranquillizers) from animal data? Part I. “Neuroleptic activity spectra” for rats

Arzneimittel-Forsch.