Pharmacological profile of the new potent neuroleptic ocaperidone (R 79,598).

Ocaperidone, a new benzisoxazolyl piperidine neuroleptic, was compared with haloperidol, risperidone and ritanserin in a large series of pharmacological tests. Ocaperidone inhibited dopamine agonist (apomorphine, amphetamine or cocaine)-induced behavioral effects at low doses (0.014-0.042 mg/kg) and was, thereby, equipotent with haloperidol (0.016-0.024 mg/kg) and 2.0 to 8.3 times more potent than risperidone. Ocaperidone completely blocked the dopamine agonist behavior at slightly higher doses (0.064 mg/kg) and was, thereby, more potent and efficacious than haloperidol (0.097-0.13 mg/kg) and risperidone (0.59-1.17 mg/kg). The dissociation between inhibition of apomorphine behavior and induction of catalepsy was as high for ocaperidone (22) as for risperidone (20) and higher than for haloperidol (8), suggesting risperidone-like low extrapyramidal side effect liability. Ocaperidone also antagonized serotonin agonist (tryptamine, mescaline or 5-hydroxytryptophan)-induced behavioral effects (0.011-0.064 mg/kg) and was, thereby, equipotent with risperidone (0.014-0.056 mg/kg) and at least as potent as ritanserin (0.037-0.13 mg/kg). Ocaperidone displayed its serotonin and dopamine antagonism at the same dose levels, in contrast to risperidone, which was a predominant serotonin antagonist. Apart from protection from compound 48/80 lethality (0.042 mg/kg) and norepinephrine lethality (0.097 mg/kg), which were not considered to hinder its clinical application, no additional secondary effects were observed at low doses of ocaperidone. In the apomorphine test in dogs, ocaperidone was very potent (i.v., s.c. and p.o. ED50 values: less than 1.0 micrograms/kg) and showed a rapid onset (less than 0.5 h) and long duration of action (24 h) after p.o. administration. Ocaperidone is concluded to be a highly potent and efficacious dopamine-D2 antagonist with concomitant, equivalent serotonin 5-HT2 antagonism. Ocaperidone is expected to exert pronounced haloperidol-like effects on the positive symptoms of schizophrenic patients but with risperidone-like low extrapyramidal side effect liability and improved patient compliance.

Ritanserin reduces abuse of alcohol, cocaine, and fentanyl in rats.

Rats that had received 3% alcohol, 0.01% cocaine, or 0.002% fentanyl as the only beverage over 10 days showed marked preference for the drug solution when water was made available as a second fluid in a separate bottle. Treatment with low doses of ritanserin, a specific central serotonin 5-HT2 antagonist, rapidly reversed drug preference without changing total fluid intake. Quantitatively, the reduction in drug consumption was greater for alcohol than for cocaine and greater for cocaine than for fentanyl. This is probably related to differences in the reinforcing potential of the three drugs.

Pharmacology of risperidone (R 64 766), a new antipsychotic with serotonin-S2 and dopamine-D2 antagonistic properties.

Comparative studies of the benzisoxazole derivative risperidone (R 64 766) were made with ritanserin, a selective centrally acting serotonin-S2 antagonist and with haloperidol, a selective centrally acting dopamine-D2 antagonist. Risperidone like ritanserin shows activity in all tests related to serotonin-S2 antagonism, but at even lower doses (peripheral S2-antagonism at 0.0011 mg/kg, central S2-antagonism at 0.014 mg/kg). Like haloperidol, risperidone shows activity in all tests related to dopamine-D2 antagonism; activity in rats for both compounds starts at 0.016 mg/kg, but some central nervous system controlled functions, including the induction of catalepsy, are relatively much less affected by risperidone. Qualitatively, risperidone is a mixed serotonin-dopamine antagonist. Quantitatively, its study in dogs reveals potent dopamine-D2 antagonistic activity with excellent p.o. bioavailability and a relatively long duration of action. From the obtained pharmacological data, risperidone could be expected to possess the complementary clinical effects of a ritanserin-like serotonin-S2 and an haloperidol-like dopamine-D2 antagonist. Serotonin-S2 antagonism may improve the quality of sleep, reduce negative and affective symptoms in schizophrenic patients and decrease extrapyramidal symptoms induced by classical neuroleptics. Because risperidone is a dopamine-D2 antagonist, antidelusional, antihallucinatory and antimanic actions are expected. The first clinical studies indicate that two additional therapeutic targets, which are not reached with classical neuroleptics, may be obtained with risperidone in the monotherapy of schizophrenia and related disorders: very important contact and mood-elevating properties and extrapyramidal symptoms-free maintenance therapy.

The antiemetic effects of domperidone, a novel potent gastrokinetic.

Domperidone is the prototype of a new chemical class of compounds with potent gastrokinetic properties. The present study reports on the antiemetic activity and safety of domperidone in dogs. The lowest ED50-values protecting from apomorphine (0.31 mg/kg s.c.) induced emesis are 0.003 mg/kg intravenously, 0.007 mg/kg subcutaneously, 0.03 mg/kg orally and 0.10 mg/kg rectally. Emesis induced by i.v. hydergine, s.c. morphine and oral levodopa is also prevented by low doses of intravenous domperidone, whereas oral copper sulphate-induced emesis is not antagonized. The doses of domperidone needed to induce central depressant effects in dogs (inhibition of conditioned reactions) are at least 300 times higher than the antiemetic doses (apomorphine-induced emesis). Domperidone is also devoid of sedative, adrenolytic and cardiovascular side-effects. The LD50-values in dogs are 42.7 mg/kg intravenously, and more than 160 mg/kg subcutaneously and orally.

Domperidone, a novel and safe gastrokinetic anti-nauseant for the treatment of dyspepsia and vomiting.

The new potent anti-nauseant 5-chloro-1-(1p[3-(2,3-dihydro-2-oxo-1H-benzimidazol-1-yl)-propyl]-4-piperidinyl)-1.3-dihydro-2H-benzimidazol-2-one (domperidone), which in contrast to available anti-emetics does not provoke extrapyramidal or adrenolytic adverse effects, also enhances gastric emptying motility. Controlled clinical trials have confirmed its prokinetic effects on the stomach and its lack of side-effects, even at high doses. This anti-nauseant appears to be a safe and effective treatment for patients, both adults and children, with dyspepsia or vomiting.

Oxatomide, a new orally active drug which inhibits both the release and the effects of allergic mediators.

Oxatomide is a new potent inhibitor of anaphylactic and allergic reactions. After oral administration, the compound both inhibits the release of endogenous histamine and prevents the effects of exogensous histamine, at comparable doses. The combination of these effects appears to be the basis of the effectiveness of oxatomide in allergic reactions and may lead to clinical application different from classical antihistaminics and from cromoglycate.

N-4-Substituted 1-(2-arylethyl)-4-piperidinyl-N-phenylpropanamides, a novel series of extremely potent analgesics with unusually high safety margin.

The intravenous analgesic activity and toxicity of a novel series of N-[4-substituted 1-(2-arylethyl)-4-piperidinyl]-N-phenylpropanamides was studied in rats. Onset, potency and duration of analgesic action were assessed in the tail withdrawal test and compared with the activity of fentanyl, (+)-cis-3-methylfentanyl (R 26 800), morphine, and pethidine. All compounds studied were found to be extremely potent analgesics characterized by an unusually high safety margin. Methyl 4-[N-(1-oxopropyl)-N-phenyl-amino]-1-(2-phenylethyl)-4-piperidinecarboxylate (R 31 833; lowest ED50 = 0.00032 mg/kg) is the most potent compound (10 031 times morphine). cis-Methyl 3-methyl-4-[N-(1-oxopropyl)-N-phenylamino]-1-(2-phenylethyl)-4-piperidine carboxylate (R 32 792) is the longest acting compound (more than 8 h at 4 times the lowest ED50) and N-[4-(1-oxopropyl)-1-[2-(2-thienyl)ethyl]-4-piperidinyl]-N-phenylpropanamide (R 33 352) is the shortest acting compound (0.74 h at 4 times the lowest ED50) of the 4-substituted fentanyl derivatives. N-[4-(Methoxymethyl)-1-[2-(2-thienyl)ethyl]-4-piperidinyl]-N-phenylpropanamide (R 30 730) was selected for further investigation. R 30 730 has a rapid onset of action and is 4521 times more potent than morphine at the time of peak effect; it has a relatively short duration of action comparable to that of fentanyl and its safety margin (LD50/lowest ED50 = 25 211) is unusually high.

Sufentanil, a very potent and extremely safe intravenous morphine-like compound in mice, rats and dogs.

Sufentanil (R 30 730), N-[4-methoxymethyl)-1-[2-(2-thienyl)ethyl]-4-piperidinyl]-N-phenylpropanamide, is a chemically novel, highly potent and extremely safe intravenous morphine-like agent in laboratory animals. In mice R 30 730 i.v. is 2304 times more potent than morphine (hot plate ED50's: 0.0028 and 6.45 mg/kg, respectively). The i.v. safety margin of R 30 730 in mice is 1 : 6 679 (LD50 = 18.7 mg/kg). Under the same experimental conditions the safety margin of pethidine is 1 : 7.97, of morphine 1 : 34.9 and of fentanyl 1 : 454. In rats R 30 730 i.v. is 4521 times more potent than morphine (tail withdrawal test ED50's: 0.00071 and 3.21 mg/kg, respectively). The i.v. safety margin of R 30 730 in rats is 1 : 25 211 (LD50 : 17.9 mg/kg). Under the latter experimental conditions the safety margin of pethidine is 1 : 4.80, of morphine 1 : 69.5 and of fentanyl 1 : 277. In dogs R 30 730 i.v. is 2429 times more potent than morphine (apomorphine antagonism test ED50's: 0.00028 and 0.68 mg/kg, respectively). The i.v. safety margin in dogs is approximately 1 : 50 000, the LD50 being +/- 14.0 mg/kg. All morphine-like effects of R 30 730 are immediately antagonized by nalorphine. These pharmacological findings are relevant in connection to the increasing interest for use of morphinomimetics in anesthesia.

Clopimozide (R 29 764), a new highly potent and orally long-acting neuroleptic of the diphenylbutylpiperidine series.

Clopimozide (R 29 764), 5-chloro-1-(4-[4,4-bis(p-fluorophenyl)butyl]-4-piperidyl)-2-benzimidazolinone, is a new member of the potent and long-acting series of diphenylbutylpiperidine neuroleptics of which pimozide is the prototype, In animals the pharmacological profile of R 29 764 resembles that of typical neuroleptic compounds. R29 764 is very potent by oral route and has an extremely long duration of action. The onset of action of clopimozide is relatively fast, it is already very potent after 4 h and, in the procedures described, reaches its peak effect 24 h after administration. In spite of the high potency and long duration of action clopimozide is relatively atoxic. The safety margin, calculated as the ratio between the acute LD50 value and the lowest ED50 value is larger than or equal to 15.000 in rats and greater than 7.250 in dogs. Qualitatively, R 29 764 is more closely related to haloperidol, pimozide and penfluridol than to chlorpromazine. The side effect liability is expected to be very low, when hypotensive, autonomic and undesirable neurological side effects are concerned.