Benzodiazepine Receptors and Their Relationship to the Treatment of Epilepsy

Abstract

Benzodiazepines (BDZ) interact with components of neuronal membranes to modify excitability in three different ways. Action at a high affinity central receptor (dissociation constant, KD, of 3 nM) linked to the GABAA recognition site enhances the inhibitory action of GABA by increasing the number of openings of Cl- channels produced by a given concentration of GABA. This effect correlates with anticonvulsant activity as evaluated in the antipentylenetetrazol test in animals and with antimyoclonic activity in human beings. It also correlates with anxiolytic activity. Action at a lower affinity membrane site (KD 100 nM to 1 microM) limits repetitive firing as observed in isolated neurons (in a manner similar to the action of phenytoin or carbamazepine). This does not depend primarily on neurotransmitter mechanisms, but probably involves an increase in the population of sodium channels in the inactive state. Action at a lower affinity site (KD 45 microM) in presynaptic terminals decreases voltage sensitive Ca++ conductance and, by limiting Ca++ entry, decreases neurotransmitter release. The two lower affinity BDZ systems may be responsible for therapeutic action in status epilepticus and for sedative side-effects. The high affinity central benzodiazepine binding sites can be differentiated into BZ1 and BZ2 receptors by ligands (such as triazolopyridazines and Quazepam) that preferentially act on BZ1 sites. There are regional differences in the density of the two receptor subtypes, but these have not yet been correlated with specific actions of benzodiazepines. Differences between various 1,4- and 1,5-benzodiazepines in terms of therapeutic action in epilepsy and neurologic side-effects can probably be explained on the basis of variation in full or partial agonist action at the high affinity central receptor, or differing relative action at the high and low affinity receptors.

Pharmacologically active compounds in the Anoectochilus and Goodyera species

“…There was no significant difference in food consumption between the normal and the control or 1-treated groups. This is in agreement with the literature [34,35]. The weight increases of the liver and the uterine fat pads were also observed in the control group, while in the 1-treated groups, they were significantly decreased.…”

Phannacokinetic‐pharmacodynamic modelling of the anticonvulsant effect of oxazepam in individual rats

“…This suggests that different mechanisms of action may be reflected in these measures of anticonvulsant effect. In this respect it is of interest that benzodiazepines can exert an anticonvulsant effect by at least 3 different mechanisms: (a) through high affinity central receptors which are linked to the GABA system, (b) through low affinity binding sites influencing sodium channels and (c) through even lower affinity binding sites which modulate voltage sensitive Ca2+ conductance (Meldrum & Chapman, 1986). The high affinity binding sites which are linked to the GABA system have convincingly been demonstrated to be involved with the antipentylenetetrazol effect of benzodiazepines (Braestrup & Nielsen, 1982).…”

GABAergic mechanisms in the pathogenesis and treatment of epilepsy.

“…Some P-carboline derivatives have a partial agonist effect at the benzodiazepine receptor and produce a powerful anticonvulsant effect with very little sedative or muscle relaxant action Meldrum & Chapman, 1986). Other 13-carboline derivatives act at the benzodiazepine receptor to produce an opposite effect to that of the benzodiazepines, decreasing the hyperpolarising action of GABA in vitro, and being anxiogenic and proconvulsant in vivo (De Deyn & Macdonald, 1987;Meldrum & Chapman, 1986). Endogenous peptides have been purified from rat, bovine and human brain that appear to act on the benzodiazepine receptor in this 'inverse agonist' fashion (Guidotti et al, 1983;Ferrero et al, 1986;Marquardt et al, 1986).…”