Hypotensive and bradycardic effects of talipexole (B-HT 920) in anaesthetized rabbits are antagonized by metoclopramide but not by yohimbine.

The interactions of talipexole (B-HT 920) and clonidine with selective alpha-adrenoceptor antagonists, yohimbine (alpha 2) and prazosin (alpha 1), as well as with dopamine receptor antagonists, metoclopramide (D2), domperidone (D2) and SCH23,390 (D1) were investigated in anaesthetized rabbits after i.v. administration. Both talipexole (0.03-0.1 mg/kg) and clonidine (0.01-0.03 mg/kg) dose-dependently induced hypotension and bradycardia. Talipexole had a shorter duration of action. The hypotensive effect of the alpha 2-adrenoceptor and D2 agonist talipexole (0.03 mg/kg) was antagonized by pretreatment with metoclopramide (3 mg/kg) or domperidone (0.3-3 mg/kg), but not with yohimbine (3 mg/kg), prazosin (0.1 mg/kg) or SCH23,390 (1 mg/kg). Its bradycardic effect was antagonized only by metoclopramide (3 mg/kg). The hypotensive and bradycardic effects of clonidine (0.03 mg/kg) were most effectively antagonized by yohimbine (0.3-3 mg/kg). These findings indicate that in anaesthetized rabbits after i.v. administration, talipexole may lower blood pressure by peripheral, and heart rate by central, dopamine D2 agonism.

Physical dependence capacity of brotizolam in rhesus monkeys. 1st communication: primary dependence studies.

Abstinence symptoms of doses acutely equi-effective on motocoordination of brotizolam (2-bromo-4-(2-chlorophenyl)-9-methyl-6H-thieno [3,2-f]-1,2,4-triazolo[4,3-a]-1,4-diazepine, We 941, Lendormin) and diazepam in rhesus monkeys were evaluated in a primary dependence study of 61 days. After termination of oral treatment with 3 X 5.4 mg/kg/d brotizolam and 3 X 13.5 mg/kg/d diazepam the duration of withdrawal symptoms varied. Most symptoms of brotizolam abstinence disappeared within 24 h of withdrawal, while the withdrawal symptoms following diazepam were more pronounced between the second and fifth day after termination of administration. Regularly during the whole study, determinations of the serum levels of brotizolam and diazepam were performed. Two days after termination of brotizolam treatment the substance could scarcely be detected in the serum. Diazepam serum levels, in contrast, declined more slowly. The physical dependence capacity of lower daily doses of brotizolam, 3 X 0.2, 3 X 0.6, and 3 X 1.8 mg/kg/d was tested in experiments with chronic administration for 4 weeks. 3 X 1.8 mg/kg/d was the lowest oral dose inducing physical dependence. Taking into consideration the great difference in human therapeutic single dosages, brotizolam is thought to have a very low physical dependence capacity in man, compared with diazepam.

Physical dependence capacity of brotizolam in rhesus monkeys. 2nd communication: primary dependence and barbital substitution.

The degree of physical dependence induced by oral administration of brotizolam (2-bromo-4-(2-chlorophenyl)-9-methyl-6H-thieno [3,2-f]-1,2,4-triazolo[4,3-a]-1,4-diazepine, We 941, Lendormin), triazolam, diazepam and nitrazepam in rhesus monkeys was evaluated in primary dependence studies. Substitution tests were performed in barbital-dependent animals. In the primary dependence studies, two dosages of each compound were administered for four weeks to compare the effects on motocoordination and development of body weight as well as the withdrawal symptoms after interruption of these chronic administrations. Taking into account the therapeutically effective doses in man, brotizolam and triazolam were tested at doses of 2 X 2 and 2 X 3 mg/kg/d. For comparison, 2 X 10 and 2 X 15 mg/kg/d of diazepam and nitrazepam were administered. Brotizolam and triazolam had a shorter duration of action than diazepam and nitrazepam. During chronic administration of brotizolam, triazolam and diazepam all animals gained body weight. Motocoordination was impaired by these compounds to a comparable degree. Nitrazepam, in contrast, was less compatible. It induced a decrease in body weight and a more pronounced disturbance of motocoordination. Only triazolam evoked effects indicating development of tolerance. Compared with the reference compounds, brotizolam induced the weakest degree of physical dependence. In the substitution tests about 2 mg/kg brotizolam, 0.6 mg/kg triazolam, 4.5 mg/kg diazepam and doses of less than 1 mg/kg nitrazepam were equipotent, suppressing withdrawal symptoms of barbital. These results demonstrate that relatively high doses of brotizolam were necessary to substitute barbital. The data obtained in rhesus monkeys are compared with the therapeutic doses in humans and discussed.(ABSTRACT TRUNCATED AT 250 WORDS)

Differentiation of mu- and kappa-receptors by means of correlation of analgesic potency in vivo and receptor binding affinity in vitro of various opioid agonists.

For various opioid agonists (n = 35) an unsatisfactory correlation between analgesic activity in vivo (mouse) and receptor binding affinity (rat brain) in vitro was obtained. Excellent correlations were observed, however, after separation of the opioid agonists into two groups with mu- and kappa-receptor selectivity, respectively. The correlation of the analgesic potency with the affinity to the opioid kappa-receptor was very high for the group of kappa-agonists, while it was low for the group of mu-agonists. The slopes of the regression lines were near unity and parallel. The shift from the less potent mu-agonists to the more potent kappa-agonists was about one order of magnitude indicating that analgesia of kappa-agonists is mediated by both mu- and kappa-receptors.

Mr 2033 CL--a novel non-morphine-like opioid analgesic.

Mr 2033 CL is a very potent non-morphine-like opioid analgesic as shown in different test models and animal species. On a weight for weight basis, it is about 20 times more potent than morphine. The analgesic effects of Mr 2033 CL are supposed to be different from those of morphine and bremazocine because of individual sensitivity against selective antagonists like naloxone and Mr 2266 CL. Mr 2033 CL does not induce the Straub tail phenomenon and increased circling movements in mice, catatonia in rats, and stupor in rabbits which are characteristic for mu agonists. Moreover, Mr 2033 CL does not have a morphine-like abuse potential in rats, dogs and rhesus monkeys. CNS-depressive effects were observed in different species. Respiratory depression and inhibition of intestinal transit seem to be of minor degree. In contrast to morphine, Mr 2033 CL provokes diuresis in rats. Binding studies in rats as well as dependence studies in rats and rhesus monkeys characterize Mr 2033 CL as a predominant kappa agonist with morphine antagonistic properties.

Pharmacology and hypnogenic properties of brotizolam in animals.

Brotizolam differs in pharmacological profile from other diazepines by virtue of its hypnogenic potency. It increases, whereas other diazepines reduce, sleep in the cat. With increasing doses, the latency to rapid eye movement sleep is lengthened and the proportion is reduced. Brotizolam has anxiolytic, anticonvulsant and muscle relaxant properties. The effective anxiolytic and muscle relaxant doses are somewhat lower than those of diazepam, and the effective anti-convulsant dose is ten times lower. Barbiturate synergism in mice is lower with brotizolam than with diazepam, while alcohol-induced coma is prolonged over the same dose range. Side-effects of brotizolam are similar to those of other diazepines, but the therapeutic range is more favourable. Physical dependence as tested in the monkey seems to be low.

Diastereoisomeric N-tetrahydrofurfurylnoroxymorphones with opioid agonist--antagonist properties.

The two diastereoisomeric N-tetrahydrofurfurylnoroxymorphones and their hydrochlorides 1a and 1b have been prepared and studied pharmacologically; The N-(R)-tetrahydrofurfuryl derivative 1a proved to be an opioid agonist--antagonist and the N-(S)-tetrahydrofurfuryl derivative 1b a pure antagonist. As an analgesic, 1a is 25 times more potent than morphine, but it does not show morphine-like side effects in mice. In withdrawn morphine-dependent rhesus monkeys, 1a only partially suppresses abstinence. Its therapeutic ratio is exceptionally favorable compared with those of morphine and pentazocine. As antagonists, 1a and 1b have comparable potencies of 0.25 and 0.20 of that of nalorphine, respectively, in vivo. In vitro, however, 1a is 28 times (guinea pig ileum) or 6.5 times (mouse vas deferens) more potent than 1b. The antagonist properties of 1a and 1b were not anticipated according to known structure--activity relationships.

[Pharmacologically active polymers. 9th communication: retard forms of morphine antagonists (author's transl)]. / Pharmakologisch aktive polymere. 9. Mitt.: Depotformen eines Morphinantagonisten.

Acryloyl, methacryloyl, N-vinylcarbamoyl, and methacryloyl-glycyl derivatives of the morphine antagonist (--)-alpha-5,9-dimethyl-2-(3-furylmethyl)-2'-hydroxy-6,7-benzomorphane have been synthesized. The different unsaturated derivatives were copolymerized with appropriate comonomers to yield water-soluble polymers. Pharmacological tests in mice showed a 2--30 fold increase in duration of action in comparison to the free antagonist. The binding of the antagonist to the polymers resulted in a reduced acute toxicity.

[General pharmacology and secretion inhibitory action of (8r)-3alpha-hydroxy-8-isopropyl-1alphaH,5alphaH-tropanium bromide-(+/-)-tropate (ipratropiumbromide) (author's transl)]. / Allgemeine Pharmakologie und sekretionshemmende Wirkung von (8r)-3alpha-Hydroxy-8-isopropyl-1alphaH,5alphaH-tropaniumbromid-(+/-)-tropat (Ipratropiumbromid)

(8r)-3alpha-Hydroxy-8-isopropyl-1alphaH,5alphaH-tropaniumbromide-(+/-)-tropate (ipratropiumbromide, Sch 1000) is a quaternary tropic acid tropane ester with pronounced anticholinergic activities (inhibition of secretion and spasmolysis). The effect of the substance of all parasympathetically innervated organs ist 1.4 to 2 times stronger than that of atropine. As an inhibitor of the secretion of free hydrochloric acid in the stomach it proved to be 5 times more effective than atropine. Central activities were not observed. The duration of action of Sch 1000 exceeds that of atropine by far.

[Study on novel morphine antagonists in the animal experiment (author's transl)]. / Prüfung einiger neuer Morphinantagonisten im Tierexperiment

The morphine-antagonistic properties of 5 novel compounds, (--)N-(3-Furylmethyl)-nordesomorphine-hydrochloride-monohydrate (Wa 494-Cl), (--)N-(3-Furylmethyl)-3-hydroxy-morphinan-methansulfonate (Mr 1257 MS), (--)2-(3-Furylmethyl)-2'-hydroxy-5,9alpha-dimethyl-6,7-benzomorphan-methansulfonate (Mr 1452 MS), (+/-)-2-(3-Furylmethyl)-2'-hydroxy-5,9alpha-diethyl-6,7-benzomorphan-hydrochloride (Mr 1302 MS), (--)-N-(3-Furylmethyl)-noroxymorphon-methanesulfonate (Mr 1767 MS), have been examined with different methods on mice and cats. Their properties have been compared with those of naloxone, cyclazocine and nalorphine. The new test compounds showed a profile of action like naloxone.

Stereoisomeric 5,9-dimethyl-2'-hydroxy-2-tetrahydrofurfuryl-6,7-benzomorphans, strong analgesics with non-morphine-like action profiles.

The eight optically active stereoisomers and the corresponding four racemic forms of 5,9-dimethyl-2'-hydroxy-2-tetrahydrofurfuryl-6,7-benzomorphan (1) have been prepared. Depending on their configurations these compounds are potent analgesics or inactive substances in mice. The analgesics attain potencies up to about a hundred times that of morphine but they do not show morphine-like side effects in mice nor do they suppress abstinence in withdrawn morphine dependent monkeys. Their therapeutic ratios are favorable and, in the case of la-1 and la-2, exceptionally good. Configuration-activity relationships are discussed. R configuration of the N-tetrahydrofurfuryl group is a major prerequisite for high analgesic potency.