Electrophysiological and pharmacological actions of the convulsant benzodiazepine Ro 5-4864 (original) (raw)
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'Peripheral-type' benzodiazepines in brain--relationship to the convulsant actions of Ro 5-4864
Previous studies have shown that Ro 5-4864 is a potent convulsant and increases the firing rate of substantia nigra zona reticulata neurons. The pharmacologic profile of compounds that antagonize these actions suggested that the effects of Ro 5-4864 were not mediated by "brain-type" benzodiazepine receptors. We examined a number of compounds that are structurally related to Ro 5-4864 for their capacities to displace [3H]Ro 5-4864 from "peripheral-type" binding sites and their potencies as convulsants (or as antagonists of Ro 5-4864-induced convulsions). It was observed that compounds such as KW 3600 (the N-desmethyl analog of Ro 5-4864), which have very low affinities for "peripheral-type" sites, are convulsants with a potency nearly equal to that of Ro 5-4864. In contrast, compounds such as Ro 5-6900 and PK 11 195. which bind with very high affinities to "peripheral-type" binding sites, are neither convulsants nor do they antagonize the convulsant actions of Ro 5-4864. Within a series of compounds that are structurally related to Ro 5-4864 there is a good correlation (r = 0.93; p < 0.01) between their potencies as convulsants and their capacities to displace [35S]t-butylbicyclophosphorothionate from sites that may be associated with the chloride ionophore. Thus, it appears that occupation of "peripheraltype" binding sites by high-affinity ligands may not be directly involved in the convulsant actions of Ro 5-4864 and related compounds. Key Words: Ro 5-4864-Convulsions-PK I 1 195-Chloride channels-t-Butylbicyclophosphorothionate. Weissman B. A. et al. "Peripheral-type'' binding sites for benzodiazepines in brain: Relationship to the convulsant actions of Ro 5-4864.
Intrinsic actions of the benzodiazepine receptor antagonist Ro 15-1788
Psychopharmacology, 1986
The imidazodiazepine Ro 15-1788 is a benzodiazepine receptor antagonist that was initially reported to be lacking in intrinsic activity in a variety of test situations in which benzodiazepine-like effects can be identified. However, many recent studies have shown that this compound does indeed have intrinsic activity in a variety of behavioural, neurological, electrophysiological and biochemical preparations in both animals and man. The purpose of the present review is firstly to describe these intrinsic actions, and secondly to consider to what extent these intrinsic actions of Ro 15-1788 have implications for current concepts of the functioning of the benzodiazepine receptor.
Neuropharmacological screening of two 1,5-benzodiazepine compounds in mice
Comptes Rendus Biologies, 2010
This work investigates whether the two 1,5-benzodiazepine compounds: 4-(2-hydroxyphenyl)-1,5-benzodiazepin-2-one (RG0501) and Benzopyrano [4,3-c] 1,5-benzodiazepine (RG0502) have any neuropharmacological activities. Diazepam and Flunitrazepam were used as drug references. The investigational 1,5-BDZ were tested in vivo for potentiating hexobarbital-induced sleep and pentylenetetrazole (PTZ)-induced seizures. Our study demonstrated that the increase of sleep duration was significantly higher with RG0501 as compared to RG0502. However, RG0502 anticonvulsant effect was more pronounced than that of RG0501 in the range dose of 6.25-37.5 mg.kg -1 . From the 50 mg.kg -1 dose, RG0502 offered a protection against clonic-tonic seizures as well as lethality (p 0.05). The results showed that the required doses to obtain a pharmacological activity were more than those of the references. This difference could be related to the lack of specific substituants responsible for the pharmacological activity in the tested compounds.
Pharmacology, Biochemistry and Behavior, 1983
In addition to anxiolytic and anticonvulsant properties, benzodiazepines (BDZ) produce sedation, ataxia, and muscular relaxation. In general, it was difficult to separate these properties within this chemical class during the search for0clinically useful anxiolytics; and when BDZ's were used to characterize :~H-BDZ binding sites they indicated only a single homogenous class of receptors. A new chemical series was discovered, triazolopyridazines (TPZ, prototype CL 218,872), which showed anticonflict activity in rats and monkeys without sedation or ataxia and inhibited :~H-BDZ binding in brain membranes with kinetic characteristics suggesting the presence of multiple BDZ receptors. High affinity and low affinity sites for the TPZ were demonstrated, the former designated at Type 1 and the latter as Type 2. Anatomical and in vivo studies have supported different distributions of each receptor in brain. Lately, the physical separation of discrete proteins which bind :~H-BDZ has been reported. The multiple receptors and the variety of endogenous substances which have been proposed as modulators and ligands of the receptors might explain variability as well as selectivity in pharmacological properties in these drugs. Recently, CL 218,872 (Fig. 1), a novel triazolopyridazine (TPZ), was reported to have selective anti-punishment and anti-convulsant activity in animals without the attendant motor depression and ataxia associated with BDZs [21,22]. Like BDZ, CL 218,872 increased punished responding and
Psychopharmacology of benzodiazepines—an update
Human Psychopharmacology-clinical and Experimental, 1995
Benzodiazepines are one of the classes of compounds which bind at the benzodiazepine site in the central nervous system. The benzodiazepine site is phylogenetically new and modulates allosterically the GABA-chloride ionophore. This complex is a pentamer surrounding the chloride channel and is made up of various combinations of alpha, beta and gamma subunits. The anatomical distribution of these subunits is diverse and underlies the differential binding of a number of benzodiazepine modulators in the brain. Other compounds which act at this complex include bicuculline, musicmol, ethanol and neurosteroids. Modulation at the benzodiazepine site is bidirectional. The net result of positive modulation is facilitation of conductance and thus hyperpolarisation i.e. an inhibitory effect, while negative modulation has the inverse effects. There is considerable receptor reserve at this complex, in addition since modulators depend on the presence of GABA for their effects, supraphysiological stimulation does not occur. These factors account for the extreme safety of benzodiazepines and explain the lack of selectivity of action of full agonists, since small increases in fractional occupancy are enough to produce the full gamut of effects. The same however does not apply to partial agonists which manifest the different actions at well separated receptor occupation. Endogenous ligands have not yet been found for these sites, although benzodiazepines have been found in brains collected prior to their pharmaceutic marketing—these probably originate from vegetable foodstuffs and gut bacteria. Changes in this site can be induced by stress, convulsions and repeated administration of modulators and animals bred for different sensitivity at the benzodiazepine site manifest consistent behavioural differences. These observations have instigated a search for potential endogenous inverse agonists in human anxiety disorders and epilepsy and for endogenous agonists in metabolic encephalopathies. While thus far this has not been successful the putative isolation of endozapines in the rare condition of idiopathic recurrent stupor indicate that this may be a useful line of research. In addition the emergence of partial agonists at these sites which have fewer side effects is likely to rekindle interest in the clinical use of such compounds in a variety of neurological and psychiatric syndromes.
Evaluation of the ?-carboline ZK 93 426 as a benzodiazepine receptor antagonist
Psychopharmacology, 1984
We describe here biochemical and pharmacological effects of the fl-carboline ZK 93426, a new and potent benzodiazepine (BZ) receptor antagonist. 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 93 426 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.
Interaction of 2,3-benzodiazepines with peripheral benzodiazepine receptors
Pharmacological research communications, 1987
2,3-Benzodiazepines (BZs), such as tofizopam (TP) and GYKI-51 189 have anxiolytic potency accompanied by moderate sedative action, but no anticonvulsant and muscle relaxant activities. These compounds show relatively low affinity to the peripheral benzodiazepine (PBZ) receptors, nevertheless, they decrease the binding of (3H)Ro5-4864 to its receptors in heart, kidney and brain membranes. This diminution in the binding is due to a decrease in the affinity for the ligand (Kd) without any change in the maximal number of binding sites (Bmax). This interaction of 2,3-BZs with PBZ binding sites may explain their pharmacological profile.