Chemistry and pharmacology of the non-benzodiazepine anxiolytic enciprazine and related compounds.

In the course of studies on tranquilizers, new non-benzodiazepine-like compounds were synthesized. These are 1-(3,4,5-trimethoxyphenoxy)-3-[4-(2-methoxyphenyl)piperazinyl]prop an-2-ol (INN: enciprazine) and derivatives thereof which were screened pharmacologically in order to evaluate their central nervous system activity. Compounds with marked antiaggressive and anxiolytic properties but without dependence potential could be detected. Enciprazine was selected for clinical investigations.

[The effect of flupirtine, various analgesics and muscle relaxants on skeletal muscle tone in the conscious rat]. / Einfluss von Flupirtin, verschiedener Analgetika und Muskelrelaxantien auf den Skelettmuskeltonus wacher Ratten.

The influence of the skeletal muscle tone by flupirtine (D-9998, Katadolon; CAS 56995-20-1), some selected analgesics and muscle relaxants was investigated in conscious rats after intraperitoneal administration. Benzodiazepines (diazepam and tetrazepam), baclofen, dantrolene and mephenesine reduced the tone of the skeletal muscle. Opiate analgesics, such as morphine, codeine and tramadol, enhanced the muscle tone. Flupirtine reduced the skeletal muscle tone at doses comparable with its antinociceptive effective doses. In this dose range no sedative side effects as ataxia or decrease of spontaneous motor activity could be observed. The mode of this muscle relaxing effect of flupirtine is not known in all details. It is, however, likely that flupirtine is able to inhibit the mono- and/or polysynaptic reflexes at the spinal level.

[New analgesically-active N'-acylated phenylpiperazines]. / Neue analgetisch wirksame N'-acylierte Phenylpiperazine.

Synthesis and pharmacodynamic properties of new analgesic active N'-acylated phenylpiperazines are described. 1-(3-Cyclohexyl-1-oxo-propyl)-4-(2-ethoxyphenyl)-piperazine (D 16 120) possesses strong non-opiate antinociceptive activity showing high therapeutic margin with respect to undesired side effects and toxicity.

[The pharmacologic effect of flupirtine, a structurally new analgesic]. / Untersuchungen zur pharmakologischen Wirkung von Flupirtin, einem strukturell neuartigen Analgetikum.

The analgesic potency of ethyl-N-[2-amino-6-(4-fluorophenylmethylamino)pyridin-3-yl]carb ama te (flupirtine, D 9998) in mice and rats in Haffner's test, electro-pain test and Randall-Selitto test (inflammation induced pain) lies between the more potent dextromoramide and methadone and the more weakly active pethidine, dextropropoxyphene, codeine, phenacetin and paracetamol. In comparison to codeine flupirtine is up to 4 times more potent, up to 2 times more active than pethidine and 4 times more potent than dextropropoxyphene in the above-mentioned methods. With one exception of inflammation induced pain, where flupirtine shows an activity of about 1 1/2 times that of phenacetin and paracetamol, both analgesics are about 10 to nearly 30 times less active than flupirtine in other above-mentioned tests. In the hot plate test flupirtine is twice as active as codeine and approximately 10 times more active than phenacetin and paracetamol. The weakest analgesic activity of flupirtine is seen in acetic acid test where it is about half as active as codein and approximately as active as dextropropoxyphene. Nevertheless, flupirtine is up to 10 times more potent than phenacetin and paracetamol. The acetic acid test is claimed to be non-specific according to our own experience and to other authors. Flupirtine is enterally absorbed at a higher degree than the other tested centrally acting analgesics. In regard to the results of various analgesic investigations in mice and rats flupirtine can be classified as a medium to strong acting analgesic. The duration of action of flupirtine is comparable to that of codeine. Experiments with flupirtine suggest that there are some convincing criteria for a pronounced central acting component of its analgesic activity. These criteria are the strong efficacy in the hot-plate and Haffner's test, in which only centrally acting analgesics show distinct effects, and the finding that flupirtine increases the pain threshold for vocalisation in rats and mice excluding a pure reflex of the spinal cord. In current experiments concerning the mode of action flupirtine exhibits a distinct central analgesic component of action. In spite of its relatively high analgesic potency which corresponds to that of opiates flupirtine does not show any other signs of opiate properties and other potent analgesics. Thus, flupirtine does not develop tolerance in mice and rats after 19 or 17 days of daily administration.(ABSTRACT TRUNCATED AT 400 WORDS)

[General pharmacologic studies on the analgesic flupirtine]. / Allgemeine pharmakologische Untersuchungen mit dem Analgetikum Flupirtin.

In the present study the general pharmacological properties of ethyl-N-[2-amino-6-(4-fluor-phenylmethylamino)pyridin-3-yl]carbama te (flupirtine, D 9998), a structural new analgesic, are described. In several tests with mice flupirtine shows a centrally depressant component of action. However, regarding undesirable side effects as ataxia, inhibition of motor activity etc. this action is, with respect to the analgesic effective doses less pronounced than those of comparable analgesics, for instance phenacetin. In relatively low doses flupirtine antagonizes tremor induced by oxotremorine in mice. This activity is probably not caused by a central anticholinergic action, because other anticholinergic effects have not been observed. It should be pointed out that flupirtine antagonizes the morphine-induced tail phenomenon in mice in relatively low doses. This action obviously differentiates flupirtine from opiates. Up to high doses flupirtine does not cause catalepsia in mice, consequently its centrally depressant activity does not resemble that of reserpine and also is not comparable with those of neuroleptic agents. The corneal and pinnal reflexes are not influenced by flupirtine and the righting reflex is slightly delayed in high doses. The anticonvulsive activity of flupirtine observed in the pentetrazol shock test (mouse) after high doses probably cannot be considered to occur within the analgesic dose range. Inhibition of amphetamine toxicity in mice observed in doses near the hypnotic doses may be caused by non-specific effects. In vitro tests with isolated trachea or ileum of guinea pigs show that flupirtine possesses no or very weak antagonism against histamine-induced spasms. In spasms caused by barium chloride flupirtine shows a weak musculotropic-spasmolytic activity. Investigations on the circulatory system of dogs do not indicate any incompatibilities with flupirtine. No evidence of antiarrhythmic activity was found in rats. Flupirtine has no local anesthetic activity in mice but some weak effects on the cornea of rabbits. Like several other analgesics flupirtine shows in rats a reversible antidiuretic action including sodium and chloride retention which is of relatively short duration and is not observed in long-term studies in rats and dogs. In contrast to many stronger antiinflammatory compounds, flupirtine does not possess ulcerogenic activity in rats up to high doses. A minimal inhibition of intestinal motility (mouse) is observed only in doses higher than the analgesic effective doses.

[Mechanism of action of the analgesic flupirtine]. / Untersuchungen zum Wirkmechanismus des Analgetikums Flupirtin.

To answer the questions of mode and site of action partly supplementary, partly new investigations with flupirtine (Katadolon) were carried out which are described below. The investigation for opiate receptor affinity of flupirtine in rat brain homogenate did not show any reduction in 3He-etorphine binding up to the highest concentration of flupirtine of 10(-5) mol/1. This result suggests that flupirtine either has a very low opiate receptor affinity or lacks it fully. Therefore the analgesic activity of flupirtine is not based on opiate mechanism. The intracerebroventricular and intrathecal administration of flupirtine and the other analgesics tested showed dose dependent analgesic activity in doses which, when applied systemically, did not cause any analgesia in rats. Thus these substances show cerebral or spinal analgesic activity. In relation to the effective doses (ED50 in micrograms/rat) flupirtine was of the same efficacy in both kinds of administration. Pethidine tested comparatively was found to be less potent by intrathecal than by intracerebroventricular application. On the other hand, morphine was weaker by intracerebroventricular than by intrathecal application. As in the experiments by oral administration, naloxone did not show any effect on the analgesic activity of flupirtine, neither by intracerebroventricular nor by intrathecal application. On the other hand, the analgesic effects of pethidine and morphine were completely suppressed by naloxone. These results demonstrate that the analgesic activity of flupirtine is not caused by the opiate mechanism.(ABSTRACT TRUNCATED AT 250 WORDS)

[The pharmacology of a new cardiosteroid, a partially synthetic derivative of the aglycone hellebrigenin (acrihellin)]. / Zur Pharmakologie eines neuen Kardiosteroids, einem partial-synthetischen Derivat des Aglykons Hellebrigenin (Acrihellin).

3 beta,5,14-Trihydroxy-19-oxo-5 beta-bufa-20,22-dienolide 3-(3-methylcrotonate) (acrihellin, D 12 316) is according to chemical structure and pharmacological effects a semisynthetic compound of the aglycon hellebrigenin. It is characterized as a cardiosteroid. In isolated organ (Langendorff heart) the positive inotropic effect proved to be stronger in comparison to digoxin. Also in dogs and cats acrihellin increases the contractile force of the myocardium; especially in failing canine heart, it increases the force of contraction (strain-gauge) and velocity of pressure rise (dp/dt max). In classical glycoside test on cat (Hatcher's dose) acrihellin is more effective than digoxin and methyldigoxin on weight basis, equivalent on a molar basis. The therapeutical index of acrihellin is like that of methyldigoxin. In cats and dogs, the compound is absorbed rapidly and almost completely, especially when administered intraduodenally. Herein it is comparable to methyldigoxin, better than digoxin. In cats acrihellin shows a decay rate of 26%. In all investigations performed in order to study central nervous effects after single administration of therapeutical doses no central side-effects could be detected in contrast to methyldigoxin.