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Biomedical subjects

W Kehr

Publications and source records attributed to W Kehr.

At least 19 recordsLinked to original sources
PubMed1990

Abecarnil, a metabolically stable, anxioselective beta-carboline acting at benzodiazepine receptors.

Abecarnil (isopropyl 6-benzyloxy-4-methoxymethyl-beta-carboline-3-carboxylate) is a novel ligand for central benzodiazepine (BZ) receptors, possessing anxiolytic and anticonvulsant properties, but with considerably reduced muscle relaxant effects in comparison to diazepam (DZP). In vitro, abecarnil inhibited the binding of the BZ [3H]lormetazepam to rat cerebral cortex membranes with an IC50 value of 0.82 nM in comparison to 56 nM for DZP. The ability of abecarnil to displace [3H]lormetazepam was enhanced 1.24-fold in the presence of 30 microM gamma-aminobutyric acid; the corresponding value for DZP was 2.8-fold. DZP and abecarnil were equally effective in enhancing the binding of t-[35S]butylbicyclophosphorothionate to rat cortical membranes. In vivo, abecarnil exhibited a 3- to 6-fold higher affinity to forebrain BZ receptors than DZP. Abecarnil was from 2 to 10 times more potent than DZP in most rodent tests of anxiolytic activity, and in reducing locomotor activity in mice and rats thoroughly habituated to the test chamber. However, in rats newly exposed to a novel cage, abecarnil was less potent than DZP in reducing locomotor activity. In tests of motor coordination, abecarnil, in contrast to DZP, showed no or only weak activity, and in potentiating the effects of ethanol and hexobarbital on motor performance abecarnil was 4 to 25 times less potent than DZP. Abecarnil antagonized the effects of BZs in the chimney and loss of righting reflex tests, but not in the rotarod test.(ABSTRACT TRUNCATED AT 250 WORDS)

Animals↗
PubMed1987

Modulation of anxiety by beta-carbolines and other benzodiazepine receptor ligands: relationship of pharmacological to biochemical measures of efficacy.

Several beta-carbolines and other benzodiazepines (BZ) receptor ligands have been investigated for anxiolytic or anxiogenic action in 4 unrelated animal models of anxiety using rats. The substances could be grouped into essentially 2 groups. The first, anxiolytics, exhibited antipunishment activity in a lick-suppression test, antagonised the discriminative stimulus provided by pentylenetetrazol, resembled chlordiazepoxide (CDP) in a drug discrimination test, and reduced the rise in plasma corticosterone levels following swim stress. Such substances included several benzodiazepines, the beta-carboline ZK 93 423, and the triazolapyridazine CL 218 872. A subgroup of anxiolytics were active in only some of these tests. They included two beta-carbolines, ZK 91 296 and ZK 95 962, and the pyrazoloquinoline CGS 9896, and these 3 substances were also distinguishable in not producing rate-decreasing effects in any of the 3 operant tests. The second group were anxiogenic in that they produced a discriminative stimulus resembling that of PTZ, they antagonised the CDP cue, exhibited propunishment effects in the lick-suppression test, and themselves caused increases in plasma corticosterone in otherwise unstressed animals. Such substances included the beta-carbolines DMCM, FG 7142 and ZK 90 886, and the pyrazoloquinoline CGS 8216. Two substances, Ro 15-1788 and ZK 93 426 had little or only weak activity in any test. The classification of these substances into anxiolytics or anxiogenics could be predicted qualitatively both by their ability to enhance (anxiolytics) or decrease the binding of 35S-TBPS to rat brain membranes and by whether their own binding was increased (anxiolytics) by adding the GABA agonist muscimol to the in vitro incubation medium. For the limited number of substances for which full data was available, there was also a quantitative relationship between the degree of enhancement of 35S-TBPS binding by a substance and its potency in the CDP cue test when such potency was expressed as numbers of BZ receptors occupied at the ED50 value in the pharmacological test. Furthermore, for the anxiolytics, activity in the CDP cue correlated significantly with potency in 2 other tests. Otherwise, surprisingly weak correlations existed between potencies in the different tests. In particular, the beta-carboline ZK 95 962 was highly potent in antagonising the PTZ cue but inactive in both a conflict test and in protecting against stress. These results are discussed in terms of differences in the neuropharmacologies of the 4 tests and in selectivity of the BZ receptor ligands for subtypes of BZ receptor.

Animals↗
PubMed1985

Evaluation of different beta-carbolines in Mongolian gerbils with reflex epilepsy.

Three benzodiazepine (BZ) receptor ligands of the beta-carboline group, namely the BZ receptor agonist ZK 93 423, the partial agonist ZK 91 296, and the antagonist ZK 93 426, were studied in epilepsy-prone Mongolian gerbils with different seizure types. Diazepam and clonazepam were included in these studies for comparison. In vivo binding studies in gerbils showed that all compounds were potent in displacing [3H]lormetazepam from binding sites in cerebellum and forebrain. Except for ZK 93 426, all drugs proved capable of dose dependently protecting gerbils from minor (myoclonic) and major (tonic-clonic) seizures induced by air blast stimulation. For ZK 93 423, ZK 91 296, diazepam and clonazepam, a highly significant correlation was found between anticonvulsant ED50S and ED50S for displacement of [3H]lormetazepam binding. Calculation of receptor occupancy revealed that beta-carbolines and benzodiazepines displayed anticonvulsant effects in gerbils at low occupancy (8-15% in forebrain). Even at almost total receptor occupancy, the BZ receptor antagonist ZK 93 426 was without any effect on seizure behaviour but antagonized the anticonvulsant effect of ZK 91 296. In contrast to diazepam, ZK 91 296 was devoid of any sedative side-effects even at 90% receptor occupancy. The data suggest that anticonvulsant beta-carbolines deserve interest as a new type of anticonvulsant drug.

Animals↗
PubMed1985

Beta-carbolines can enhance or antagonize the effects of punishment in mice.

Six beta-carboline ligands at central benzodiazepine (BZ) receptors were tested for their anxiolytic or anxiogenic properties in mice in the four-plate test. ZK 93 423 and ZK 91 296 increased activity which had been suppressed by punishment (1 mA, 60 ms footshock) at doses which exerted no effect on unpunished locomotion. ZK 93 426, ZK 90 886, FG 7142, and DMCM exerted no antipunishment activity themselves, and antagonized the ability of diazepam to increase both punished and unpunished locomotor activity. DMCM, FG 7142, and ZK 90 886, but not ZK 93 426, also enhanced the ability of a reduced level of footshock (0.3 mA) to suppress activity. This propunishment activity of DMCM and ZK 90 886 took place at doses which had no effect on unpunished locomotion. The nature of the effect of the individual beta-carbolines on punishment was related to the nature of their interaction with the BZ/GABA receptor/chloride channel complex (GBC complex). Thus the antipunishment properties of ZK 93 423 and ZK 91 296 were associated with their ability to increase binding of 35S-t-butylbicyclo-phosphorothionate (TBPS) to its binding site associated with the chloride channel, whereas DMCM, FG 7142 and ZK 90 886, which exerted propunishment effects, reduced TBPS binding. ZK 93 426, which was neutral with respect to punished activity, had the weakest effect on TBPS binding. These results are discussed in the context of a possible role of GBC complex in anxiety.

Animals↗
PubMed1985

Effects of rolipram, a novel antidepressant, on monoamine metabolism in rat brain.

The phosphodiesterase inhibitor and putative antidepressant rolipram (0.3-30 mg/kg i.p.) stimulated the accumulation of dopa following inhibition of the aromatic amino acid decarboxylase with 3-hydroxybenzylhydrazine HCl dose-dependently in all brain regions investigated, suggesting that both dopamine and noradrenaline synthesis was enhanced. The stimulatory effect of rolipram on dopa accumulation in dopamine rich regions persisted even after pretreatment with gamma-butyrolactone which by itself increased dopa accumulation three fold. Following inhibition of catecholamine synthesis with alpha-amethyl-p-tyrosine rolipram accelerated the disappearance of noradrenaline and slowed the disappearance of dopamine. At low doses rolipram tended to reduce the pargyline-induced accumulation of 3-methoxytyramine. Rolipram attenuated the accumulation of 5-hydroxytryptophan in the neocortex and the diencephalon of 3-hydroxybenzylhydrazine HCl pretreated rats. The data suggest that rolipram enhances noradrenergic transmission by direct stimulation of tyrosine hydroxylase and by an increase of neuronal activity. Despite a stimulatory effect on tyrosine hydroxylase rolipram does not appear to alter dopamine release and metabolism to a large extent. In view of the occurrence of head-twitches the rolipram-induced reduction of 5-hydroxytryptamine metabolism may be due to feedback inhibition.

Animals↗
PubMed1985

Receptor-mediated regulation of 5-hydroxytryptamine metabolism: current knowledge and open questions.

As demonstrated for the catecholamine system several receptor-mediated mechanisms appear to be involved in the regulation of serotonergic transmission, though regulatory processes of serotonergic transmission are less well investigated as compared with the catecholamine system. One of the main homeostatic mechanisms appears to be neuronal feedback mediated by postsynaptic 5-HT receptors. The constituents of the neuronal feedback loop are unknown at present. In addition to neuronal feedback, an autoreceptor-mediated feedback appears to exist. According to their localization, 5-HT autoreceptors can be subdivided into somatodendritic and presynaptic autoreceptors. Stimulation of somatodendritic 5-HT receptors leads to inhibition of the firing rate, and stimulation of presynaptic autoreceptors in vitro to inhibition of impulse-induced release of 5-HT. Further to 5-HT receptors, other transmitter receptors appear to exist on presynaptic nerve terminals which may either inhibit or facilitate 5-HT release. The physiological significance of all these presynaptic receptors remains to be shown. The evaluation of feedback mechanisms controlling 5-HT neurons is hampered by the fact that no selective central 5-HT antagonists are available at present. There is an urgent need for selective receptor antagonists for 5-HT autoreceptors as well as postsynaptic receptors. Binding studies have revealed at least two subtypes of 5-HT receptors, 5-HT1 and 5-HT2 receptors. Selective 5-HT1 and 5-HT2 agonists and antagonists are needed in order to characterize these receptors subtypes and to find their functional correlates.

Animals↗
PubMed1984

Beta-carbolines with agonistic and inverse agonistic properties at benzodiazepine receptors of the rat.

The anxiogenic or anxiolytic properties of five beta-carbolines were assessed in rats trained in two-lever operant chambers to operate one lever to obtain food reward when treated with a training drug, and the other when treated with saline. Two such drug-discrimination tests were used, employing either chlordiazepoxide (CDP) or pentylenetetrazol (PTZ) as training drugs. The benzodiazepine (BZ) agonist, ZK 93 423, substituted for the CDP cue and antagonized the PTZ cue. The inverse agonists DMCM and FG 7142 showed the opposite effects. An antagonist, ZK 93 426, antagonized the CDP cue but did not substitute for PTZ, while a partial agonist was identified as CDP-like but only partially antagonized the PTZ cue. An anxiolytic profile (substitution for CDP and antagonism of PTZ) was associated with GABA ratios of about 2, and an anxiogenic profile with GABA ratios less than 1. The antagonist and partial agonist displayed intermediate values. These observations are generally consistent with the beta-carbolines modulating anxiety through their activity at BZ receptors influencing GABAergic neurotransmission.

Animals↗
PubMed1984

Transdihydrolisuride, a partial dopamine receptor antagonist: effects on monoamine metabolism.

The 9,10-transdihydro analogue of the dopaminergic ergot derivative lisuride, transdihydrolisuride (TDHL) stimulated the accumulation of dopa following inhibition of the aromatic amino acid decarboxylase with 3-hydroxybenzylhydrazine HCl in striatum (0.1-10 mg/kg i.p.), in the dopamine rich part of the limbic system (at 3 mg/kg i.p.) and in the neocortex (0.3-10 mg/kg i.p.). At a low dose (0.03 mg/kg) however, TDHL inhibited dopa accumulation in the limbic system. In gamma-butyrolactone-pretreated rats TDHL not only inhibited the accumulation of dopa in striatum and in the dopamine-rich part of the limbic system but also antagonized the inhibitory effect of lisuride on dopa accumulation. The accumulation of 5-hydroxytryptophan was reduced in striatum, in parts of the limbic system and neocortex only at high doses of TDHL (3 and 10 mg/kg i.p.). TDHL (0.03 or 3 mg/kg i.p.) did not change the alpha-methyl-p-tyrosine methylester HCl-induced disappearance of dopamine but accelerated the disappearance of noradrenaline at a dose of 3 mg/kg in all brain regions studied. The striatal level of dihydroxyphenylacetic acid was increased by TDHL dose dependently, the maximum effect being only half of that induced by haloperidol. TDHL (0.3 and 3 mg/kg i.p.) stimulated the accumulation of 3-methoxytyramine and normetanephrine following monoamine oxidase (MAO) inhibition with pargyline. The data suggest that TDHL is a mixed agonist-antagonist at central dopamine receptors. Under normal conditions the antagonistic component appears to predominate in the nigrostriatal and mesolimbic system. The stimulation of noradrenaline turnover was most likely due to an adrenoceptor antagonistic action of TDHL.

3,4-Dihydroxyphenylacetic Acid↗
PubMed1984

Discriminative stimulus properties of beta-carbolines characterized as agonists and inverse agonists at central benzodiazepine receptors.

The discriminative stimulus properties of three beta-carboline derivatives were studied in three groups of rats trained, respectively, to discriminate diazepam (2.5 mg/kg IP), chlordiazepoxide (CDP, 5 mg/kg IP) or pentylenetetrazol (PTZ, 15 mg/kg IP) from saline in standard procedures employing two-lever operant chambers. Two beta-carbolines, ZK 91296 and ZK 93423, substituted for the benzodiazepines in both CDP- and diazepam-trained rats. The neutral benzodiazepine antagonists Ro 15-1788 blocked the diazepam discriminative stimulus and the ability of ZK 91296 to substitute for diazepam. A third beta-carboline, FG 7142, was not identified as benzodiazepine-like in generalization tests in either diazepam- or CDP-trained rats, but when administered together with CDP antagonized the benzodiazepine discriminative stimulus. In rats trained to discriminate PTZ from saline (a discrimination which is thought to depend on the anxiogenic properties of PTZ) the PTZ cue was antagonized by diazepam and ZK 93423, and partially antagonized by ZK 91296. The PTZ cue generalized to FG 7142 and this generalization was partially antagonized by Ro 15-1788. These results suggest that the three beta-carbolines provide more than one kind of discriminative stimulus, consistent with the classification of ZK 93423 as an agonist at central benzodiazepine receptors, with ZK 91296 as a partial agonist, and with FG 7142 as an inverse agonist. Pharmacologically, ZK 93423 and ZK 91296 may exhibit anxiolytic qualities, whereas FG 7142 produces anxiogenic effects.

Animals↗
PubMed1984

ZK 91296, a partial agonist at benzodiazepine receptors.

5-benzyloxy-4-methoxymethyl-beta-carboline-3-carboxylate) is a potent and selective ligand for benzodiazepine (BZ) receptors. Biochemical investigations indicate that ZK 91296 may be a partial agonist at BZ receptors. Such partial agonism may explain to some extent why ZK 91296 needs higher BZ receptor occupancy than diazepam for the same effect against chemical convulsants and for behavioural effects. The lack of sedative effects, and the very potent inhibition of reflex epilepsy, spontaneous epilepsy and DMCM-induced seizures suggest, furthermore, that ZK 91296 may possess pharmacological selectivity for a particular type of BZ receptor interaction, perhaps including topographic as well as receptor subtype differentiation.

Animals↗
PubMed1984

Evaluation of the beta-carboline ZK 93 426 as a benzodiazepine receptor antagonist.

We describe here biochemical and pharmacological effects of the beta-carboline ZK 93426 was compared with Ro 15-1788 and CGS 8216, two compounds previously described as BZ receptor antagonists. Certain effects of ZK 93426, Ro 15-1788 and CGS 8216 were quite similar (e.g., 3H-FNM displacement, "GABA ratio", "photo-shift"). In most pharmacological tests ZK 93426 and Ro 15-1788 lacked overt effects; Ro 15-1788 was a weak agonist in some paradigms, while ZK 93426 exhibited a potent proconflict effect but also a weak anticonvulsant effect. This interesting finding with ZK 93426 suggests that BZ receptor ligands may possess differential efficacy at BZ receptor subtypes. In contrast, CGS 8216 exhibited potent proconvulsant effects in several paradigms in addition to proconflict and pentylenetetrazol generalizing effects. ZK 93426, Ro 15-1788 and CGS 8216 were almost equally potent as antagonists of the effects of BZ receptor agonists, such as diazepam and lorazepam. However, ZK 93426 was the most potent inhibitor of the convulsions produced by the BZ receptor inverse agonist DMCM.

Animals↗
PubMed1983

Central antidopaminergic properties of 2-bromolisuride, an analogue of the ergot dopamine agonist lisuride.

2-Bromolisuride (2-Br-LIS), a derivative of the ergot dopamine (DA) agonist lisuride, was investigated in rodents in comparison with the DA antagonist haloperidol with regard to its influence on DA related behaviour, cerebral DA metabolism and prolactin (PRL) secretion. 2-Br-LIS produced catalepsy in mice (ED50 3.3 mg/kg i.p.), antagonized apomorphine-induced stereotypies in mice (ED50 0.4 mg/kg i.p.), antagonized DA agonist-induced stereotypies in rats (0.1-1.56 mg/kg i.p.), inhibited locomotor activity in rats (0.025-6.25 mg/kg i.p.), antagonized the hyperactivity produced by various DA agonists in rats (0.025-6.25 mg/kg i.p.) and inhibited the apomorphine-induced hypothermia in mice (0.05-0.78 mg/kg i.p.). 2-Br-LIS (0.03-10 mg/kg i.p.) stimulated DA biosynthesis and DOPAC formation in the striatum and DA rich limbic system of rats, but had no effect on serotonin turnover. In striatum and limbic forebrain of gamma-butyrolactone-pretreated rats 2-Br-LIS reversed the apomorphine-induced inhibition of DOPA accumulation. 2-Br-LIS (0.03 - 3 mg/kg) enhanced PRL secretion in intact male rats. These findings indicate DA antagonistic properties of 2-Br-LIS presumably due to blockade of central pre- and postsynaptic DA receptors being of approximately the same order of potency as haloperidol. 2-Br-LIS is the first ergot compound with definite antidopaminergic properties suggesting its potential usefulness as a neuroleptic.

3,4-Dihydroxyphenylacetic Acid↗
PubMed1982

Does the reversal of the anticonflict effect of phenobarbital by beta-CCE and FG 7142 indicate benzodiazepine receptor-mediated anxiogenic properties?

In mice and rats, the high affinity ligand for brain benzodiazepine (BZ) receptors beta-CCE, and the more stable congener FG 7142, failed to exert anticonflict activity in conflict situations but instead reversed the anticonflict effect of lorazepam. In contrast to Ro 15-1788, beta-CCE and FG 7142 also antagonized the anticonflict effect of phenobarbital in rats. This effect suggests that beta-CCE and FG 7142 may produce anxiety by either inducing a conformational change in the BZ receptors which is directly opposite to that induced by the benzodiazepines, or binding to a particular subclass of BZ receptors.

Animals↗
PubMed1982

Catecholamine metabolism in rat brain following the intracerebroventricular administration of cyclic nucleotides.

The dibutyryl analogues of cyclic adenosine monophosphate (cAMP) and cyclic guanosine monophosphate (cGMP) were administered into the lateral ventricles and catecholamine metabolites were determined in brain 40 min later. Dibutyryl cAMP elevated the level of homovanillic acid in whole brain and dihydroxyphenyl acetic acid levels in striatum, the dopamine-rich part of the limbic system and hemispheres but neither affected the accumulation of 3-methoxytyramine following inhibition of MAO with pargyline nor dopamine and noradrenaline levels. Normetanephrine accumulating after MAO inhibition was elevated markedly by dibutyryl cAMP. Dibutyryl cGMP was without effect on the catecholamine metabolites investigated. Dibutyryl cAMP appears to stimulate dopamine metabolism within dopaminergic nerve endings but does not stimulate dopamine release. Dibutyryl cAMP-induced activation of noradrenaline metabolism, however, appears to coincide with a stimulation of noradrenaline release.

3,4-Dihydroxyphenylacetic Acid↗