Benzodiazepine Partial Agonist Research Articles

Local administration of flurazepam has different effects on dopamine release in striatum and nucleus accumbens: A microdialysis study

The action of local administration of flurazepam on extracellular levels of dopamine (DA) and its metabolites 3,4 dihydroxyphenyl acetic acid (DOPAC) and homovanillic acid (HVA) in the anterior striatum and medial nucleus accumbens have been investigated using microdialysis. Flurazepam (10 μM), administered through the perfusion medium for 20 min, reduced levels of DA in dialysates from the nucleus accumbens by 60% while the same concentration of the drug had no effect on levels of DA in perfusates from the striatum. Pretreatment with the benzodiazepine antagonist Ro 15-1788 (flumazenil) or with picrotoxin, a drug which blocks the GABA A receptor-associated chloride channel, inhibited the effect of flurazepam on levels of DA in the nucleus accumbens, which suggests that the effect was mediated by the multimolecular GABA A/benzodiazepine receptor complex. Administration of flurazepam had little effect on the two metabolites of DA, DOPAC and HVA, in either the nucleus accumbens or striatum. The inverse partial benzodiazepine agonist, FG 7142, had no significant action on the release of DA in the nucleus accumens. These results suggest that the dopaminergic projection to the nucleus accumbens is more sensitive to benzodiazepine-induced inhibition than the projection to the striatum.

Flumazenil. A preliminary review of its benzodiazepine antagonist properties, intrinsic activity and therapeutic use.

Flumazenil, a 1,4-imidazobenzodiazepine, is a specific benzodiazepine antagonist which is indicated for use when the effect of a benzodiazepine must be quickly attenuated or terminated. Following intravenous administration, the onset of clinically apparent benzodiazepine antagonism usually occurs within 1 to 5 minutes. Although flumazenil has a short elimination half-life of about 1 hour, a single intravenous dose of up to 1 mg is usually sufficient to attain and maintain for about 2 hours the desired level of consciousness after general anaesthesia or conscious to moderate sedation induced by benzodiazepines. After intoxication with high doses of benzodiazepines the initial single dose of flumazenil will require supplementing with repeated low intravenous doses or an infusion (0.1 mg/h) to maintain a state of wakefulness. Flumazenil is well tolerated, and since it reliably attenuates or reverses the central effects of benzodiazepines and is specific for these drugs, it facilitates diagnosis by eliminating benzodiazepine intoxication in patients in whom the cause of unconsciousness is unknown. While results of some studies suggested that flumazanil may have intrinsic benzodiazepine partial agonist or inverse agonist activity, this is unlikely to be clinically important with usual doses. Thus, flumazenil is a very promising, effective, short acting benzodiazepine antagonist which is well tolerated by most patients. Undoubtedly, its full clinical potential has yet to be realised.

The benzodiazepine partial agonists, Ro16-6028 and Ro17-1812, increase palatable food consumption in nondeprived rats

Two novel imidazobenzodiazepines, Ro16-6028 and Ro17-1812, have been described recently as partial agonists acting at benzodiazepine receptors. In a test of palatable food consumption using nondeprived rats, Ro16-6028 (0.01−10 mg/kg) and Ro17-1812 (0.01−10 mg/kg) were shown to produce dose-dependent increases in food intake. Ro16-6028 was more potent than Ro17-1812. Suriclone, midazolam, and the β-carbolines ZK 93423 and ZK 91296 also significantly increased food intake. The maximum effects of Ro16-6028 and Ro17-1812 were at least equivalent to those obtained with full agonists acting at benzodiazepine sites. Neither Ro16-6028 nor Ro17-1812 reduced locomotion or rearing frequency in an open field test, although there was a reduction in grooming frequency. In contrast, the full agonist midazolam dose-dependently reduced all measures of general activity. The results indicate that some novel benzodiazepine partial agonists strongly stimulate food intake in the absence of side effects typical of the classical benzodiazepines.

Clinical perspectives of β-carbolines from first studies in humans

First results from studies in healthy subjects with the β-carbolines ZK 91 296, ZK 95 962 and ZK 93 426 are reviewed. ZK 91 296 and ZK 95 962, characterized as partial benzodiazepine agonists in preclinical research, were unable to induce some typical benzodiazepine effects like sedation when administered intravenously in high doses. ZK 95 962, reported to be effective in photoepileptic patients, was able to reverse lormetazepam-induced sleep as documented by EEG-parameters. The benzodiazepine receptor antagonist ZK 93 426 dose-dependently elicited alertness, restlessness and mild apprehension—symptoms opposite those known for the benzodiazepines. The activating effect of ZK 93 426 was confirmed by the results from, e.g., self-rating scales and the logical reasoning test. In another placebo-controlled study comparing the effects of ZK 93 426 alone and in combination with lormetazepam vigilosomnograms obtained after ZK 93 426 alone clearly confirmed the activating effect. In combination with lormetazepam ZK 93 426 was able to reverse the benzodiazepine induced sleep. The attenuation of benzodiazepine effects was also evident from multiple sleep latency tests. Our results support findings from animal experiments which classify these β-carbolines as benzodiazepine receptor ligands with partial agonist and antagonist properties. β-Carbolines may prove to be beneficial drugs in the treatment of anxiety, convulsions and diseases with an impairment of cognitive functions as well as in the reversal of unwanted benzodiazepine effects.

Novel benzodiazepine receptor ligands stimulate intake of hypertonic NaCl solution in rehydrating rats

Experiments were conducted to determine the degree of generality of previous findings that anxiolytics increased the ingestion of hypertonic saline in rehydrating rats. Further, potential differential effects amongst recently described benzodiazepine receptor partial agonists were explored. Finally, the hypothesis that benzodiazepine receptor partial inverse agonists would decrease the ingestion of hypertonic NaCl solution was tested. Results indicated that full agonists (midazolam, ZK 93423, zopiclone) produced substantial dose-related increases in hypertonic saline comsumption. The putative 5-HT 1A agonist, buspirone, produced only a dose-dependent decrease in saline intake. Partial agonists fell into two distinct categories: ZK 91296, CL 218,872 and two novel benzodiazepines, Ro16-6028 and Ro17-1812, also increased saline ingestion. In contrast, two pyrazoloquinolines, CGS 9896 and CGS 9895, had no significant effect on intake. Two compounds, CGS 8216 and FG 7142, described as benzodiazepine partial inverse agonists, did not significantly affect consumption of the hypertonic saline.

CGS 8216, a benzodiazepine antagonist, reduces food intake in food-deprived rats.

CGS 8216, a benzodiazepine receptor antagonist with weak inverse agonist properties, reduced food intake in food-deprived rats when administered orally or intraperitoneally at doses that antagonize diazepam. This effect was sustained when CGS 8216 was administered daily for five days, indicating no rapid tolerance to the anorectic effect. Ro 15-1788 did not reduce feeding when administered orally, and was active only at high intraperitoneal doses (54 and 100 mg/kg). CGS 9896, a close analog of CGS 8216 but a benzodiazepine partial agonist with anxiolytic properties, did not reduce food intake at doses as high as 100 mg/kg IP or PO. These results support prior suggestions that benzodiazepine receptors may modulate feeding behavior, and suggest that CGS 8216 may have appetite suppressant properties.

Benzodiazepine inhibition of [ 3H]flunitrazepam binding and caffeine-induced seizures in mice

The median inhibitory and anticonvulsant potencies of seven benzodiazepine (BDZ) agonists and one BDZ antagonist (Ro15-1788) were established by two tests: inhibition of [ 3H]flunitrazepam receptor binding and prevention of caffeine-induced seizures in mice. The effect of Ro15-1788 on the anticonvulsant potency of diazepam against caffeine-induced seizures was also investigated. The [ 3H]flunitrazepam receptor binding inhibitory potencies (IC 50s) of the BDZ agonists correlate well with their anticonvulsant potencies (ED 50s) against caffeine-induced seizures (r = 0.831; P > 0.01 and < 0.05). Ro15-1788 and clonazepam are the most potent inhibitors (IC 50s: 1.72 and 1.75 nM, respectively), but differ markedly in their ability to obtund caffeine-induced seizures (ED 50s: 43.2 and 0.226 mg/kg, respectively). Although both Ro15-1788 and diazepam are effective against caffeine-induced seizures, when used in combination Ro15-1788 antagonizes the anti-caffeine effect of diazepam. These data indicate that Ro15-1788 is a BDZ partial agonist with low efficacy as well as a potent antagonist.

Enhancement of GABA binding by the benzodiazepine partial agonist CGS9896

Compounds have been reported that act on the benzodiazepine receptor as full agonists (diazepam and CL218872), full antagonists (CGS8216 and RO15-1788), on partial agonists (CGS9896). We examined the effect of these compounds on [3H]GABA binding to membrane fragments from rat brain. Incubations were performed at 37 degrees C in a buffer containing EGTA to reduce free calcium ion levels. Centrifugation was then used to separate bound from free [3H]GABA. Diazepam caused a 20-45% enhancement of [3H]GABA binding and this effect was inhibited by 5 mM CaCl2. The magnitude of the enhancement of [3H]GABA by CL218872 was similar to that of diazepam. In contrast, the benzodiazepine antagonists, RO15-1788 and CGS8216 caused little enhancement of [3H]GABA binding. Finally, the partial agonist CGS9896 was distinguishable from both the benzodiazepine antagonists and full agonists by an intermediate level of enhancement of [3H]GABA binding. The extent of enhancement of [3H]GABA binding appears to be predictive of the pharmacological efficacy of compounds acting at the benzodiazepine receptor.