BZ receptors

A newel class of hypnotic at the pieclinical stage as of this writing (ca 1993) are the neuiosteioids, also known as the epalons and represented by (30) (9), interact with the GABA /BZ receptor complex, have shown interesting activity in preclinical models (10), and are... 

Benzodiazepines. Several BZs have anticonvulsant activity and ate used for the treatment of epilepsy producing their anticonvulsant actions via interactions with the GABA /BZ receptor complex to enhance inhibitory GABAergic transmission (1). The anticonvulsant actions of the BZs tend to tolerate upon chronic usage in six months, and BZs also lead to withdrawal symptomatology. Other side effects include sedation, ataxia, and cognitive impairment. 

Nonbenzodiazepine Benzodiazepine Receptor Ligands. The simultaneous discovery of the molecular target for the BZs, the GABA /BZ receptor complex, by two teams of workers (34,35) resulted ia the identification of a number of atypical or anxioselective anxiolytics that, whereas not having the BZ pharmacophore, interacted direcdy with the central BZ receptor. The anxioselective nature of such agents was considered to be... 

The PBRis distinct from the central BZ receptor although both can be present in the same tissues in differing ratios. PBRs are predominately localized on the outer mitochondrial membrane and are thus intracellular BZ recognition sites. The PBR is composed of three subunits an 18,000 mol wt subunit that binds isoquinoline carboxamide derivatives a 30,000 mol wt subunit that binds BZs and a 32,000 mol wt voltage-dependent anion channel subunit. The porphyrins may be endogenous ligands for the PBR. PBRs are involved in the control of cell proliferation and differentiation and steroidogenesis. 

Gannabinoids. Like the BZ receptor, the cannabinoid receptor was initially identified using psychotropic alkaloids such as A -tetrahydrocannabinol (A-THC) (78) that were known to affect mammalian CNS function (see PsYCHOPHARMACOLOGiCALAGENTs). The CNS receptor,... 

In addition to its interaction with central BZD receptors, pharmacological concentrations of melatonin can also bind to the peripheral-type BZ receptors (PBRs), which are involved in neurosteroidogenesis (Garcia-Ovejero et al. 2005). PBRs are primarily localized on the outer mitochondrial membrane these sites are therefore also referred to as mitochondrial BZD receptors. Using the isoquinoline carboxamide, PK14105, for photoaffinity labelling, an 18 kDa isoquinoline... 

Pharmacology Zolpidem is a nonbenzodiazepine hypnotic. While zolpidem is a hypnotic agent with a chemical structure unrelated to benzodiazepines, barbiturates, or other drugs with known hypnotic properties, it interacts with a GABA-BZ receptor complex and shares some of the pharmacological properties of the benzodiazepines. 

The BZ binding site of the GABA receptors have been further classified into three types, (Oj.j, based on their location in the CNS and their ability to bind different compounds. A fourth type of BZ receptor, peripheral-type BZ receptors, occurs in the peripheral tissues as well as the CNS. The function of this type of receptor remains unknown (To et ah, 1983 Ballenger, 1995). 

The main effects of BZs occur via positive allosteric modulation. The BZs and GABA bind to separate sites on the GABAa receptor complex. When a BZ occupies the BZ receptor, GABA s ability to open the chloride channels increases. With greater opening of the chloride channel, cellular excitability decreases (Ballenger, 1995). The final result of this decreased cellular excitability is widespread because of the extensive inhibitory role of GABA in the CNS. As a result, BZs may alter the turnover of neurotransmitters such as norepinephrine and serotonin (5-hydroxytryptamine [5-HT]). 

Zolpidem interacts with coj BZ receptors, but only exhibits weak binding to the CO2 and CO3 subtypes. Like the BZs, Zolpidem appears to potentiate GABAergic transmission (Lantry and Benfield, 1990 Salva and Costa, 1995). 

Da Settimo F et al GABA A/Bz receptor subtypes as targets for selective drugs. Curr Med Chem 2007 14 2680. 

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. 

A model of the hypothetical GABA-BZ receptor-chloride ion channel macromolecular complex is shown in Figure 22-5. 

The physiologic significance of endogenous modulators of the functions of GABA in the central nervous system remains unclear. To date it has not been established that the putative endogenous ligands of BZ receptors play a role in the control of states of anxiety, sleep patterns, or any other characteristic behavioral expression of central nervous system function. 

Studies have shown a reduced density of lymphocyte BZ receptor sites (119) and platelet BZ sites in GAD patients, which was increased following diazepam treatment (120). These peripheral receptors are pharmacologically distinct tfom the central GABA receptors, so the relevance of these studies to anxiety is unclear. More relevant may be the study cf central BZR activity in anxiety patients. Reduced BZR sensitivity has been shown in GAD patients by measuring saccadic eye movements (121,122). This effect was even more pronounced in patients with panic disorder G23), but was absent in OCD (124). These studies suggest that there may be a reduced BZ receptor function in some anxiety disorders. 

The interaction between the subunits and the Bz receptor ligand provides for a wide range of allosteric regulation of chloride ion flux within the associated ion channel (112,... 

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