Full agonists benzodiazepines

TABLE 29-1. Pagoclone versus full agonist benzodiazepines ... 

FIGURE 8-26. The benzodiazepine (BZ) receptor antagonist flumazanil is able to reverse a full agonist benzodiazepine acting at the benzodiazepine receptor of the GABA A receptor complex. This may be helpful in reversing the sedative effects of full agonist benzodiazepines when administered for aesthetic purposes or when taken in an overdose by a patient. 

If a full agonist benzodiazepine reduces anxiety, it would follow that an inverse agonist benzodiazepine would actually produce anxiety. 

A series of 2-phenyl [ 1,2,3 triazolo[l,2-tf][l,2,4]bcnzotriazin-l,5(6//)-diones display submicromolar/nanomolar potency at the central benzodiazepine receptor. The most potent compound 687 (Kj= 2.8 nM) with enhanced affinity is a full agonist at al and aZ receptor subtypes, and has an antagonist efficacy at a5 receptors <2005JME2936>. 

A series of imidazo[l,5-a]quinoxaline amides, carbamates, and ureas which have high affinity for the y-aminobutyric acid A/benzodiazepine receptor complex was developed. Compounds within this class have varying activities ranging from antagonists to full agonists. However, most analogs were found to be partial agonists as indicated by [ S]TBPS and Cl current ratios. Many of these... 

Zopiclone. Zopiclone is a full agonist that has been shown to have sedative properties in experimental animals and to be a potent hypnotic in humans. It has a short duration of action and minimal effects on sleep architecture, which means that it has few residual effects on waking. It appears to cause less tolerance and problems on withdrawal than the classic benzodiazepines and is currently marketed as a hypnotic. 

This can translate into opposite behavioral actions for agonists versus inverse agonists. For example, benzodiazepine full agonists reduce anxiety by increasing chloride conductance, as shown in Figure 8—23- However, a benzodiazepine inverse agonist causes anxiety and does this by decreasing chloride conductance, as shown in... 

FIGURE 9—4. Another theory about the biological basis of panic disorder is an abnormality in the set point for benzodiazepine receptors. Perhaps the sensitivity of these receptors is switched to the left in this spectrum, rendering the receptors less sensitive to full agonists and experiencing antagonists as inverse agonists. 

Partial agonists at benzodiazepine receptors As discussed for general anxiolytic agents in Chapter 8, the partial benzodiazepine agonists could be a theoretical advance over the marketed benzodiazepines. Partial agonists should have the same efficacy as full agonists but less potential for sedation, dependence, and withdrawal effects. 

Zaleplon has a pharmacological profile similar to benzodiazepines. Zaleplon is a full agonist for the benzodiazepine oq receptor located on the GABAa receptor ionophore complex in the brain, with lower affinity for the a2 and a3 subtypes. It selectively enhances the action of GABA similar to but more selectively than benzodiazepines. Zaleplon, although not benzodiazepine-like in chemical structure, induces sedative-hypnotic, anticonvulsant, and anticonflict effects via its binding to the central nervous system (CNS)-type benzodiazepine receptors [33-36]. 

From the published clinical studies, it would appear that the partial agonists bretazenil and abercamil are less likely to cause physiological dependence, have lower reinforcing effects and a lower incidence of subjective effects associated with abuse liability than the conventional 1,4-benzodiazepine sedative-hypnotics. It is presently unclear whether the full agonists for the GABA-A receptor, zolpidem and zopiclone, offer a real advance in the treatment of insomnia although their adverse effect profiles and abuse liability may be lower than that of the conventional benzodiazepines. 

Other nonreceptor site of action interactions include MAOIs - pethidine (acute dystonias), ethanol - benzodiazepines (synergisitic sedation and respiratory depression), cocaine - amphetamines (hypertensive crisis) and dihydrocodeine -morphine (the former is a partial agonist and reduces the efficacy of the full agonist). 

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