Figure 3 GABAa receptor. (a) Horizontal cross-section through the GABAa receptor showing the pentameric arrangement of two a subunits, one p subunit, and one g subunit to form the central chloride permeable channel. Arrows indicate the two recognition sites for GABA at the a/p interface and the benzodiazepine (Bz) binding site at the a/g interface. (b) Vertical cross-section.

(chlorpromazine, meprobamate, and reserpine). Chlordiazepoxide eventually was tested as a result of a laboratory clean up and an interest in publishing the chemistry. The compound ultimately proved active in animal models used to test for tranquilizers and its structure was accurately determined. Ultimately, chlordiazepoxide was evaluated successfully in the clinic and two and a half years elapsed between the first in vivo test and its commercial launch.

BZs interact with the GABAa ligand-gated ion channel. GABA is the primary inhibitory neurotransmitter in the mammalian CNS. The effect of synaptically released GABA on receptive neurons is to inhibit neuronal activity through activation of the GABAA receptor to increase the postsynaptic chloride ion permeability of the cell leading to hyperpolarization of the membrane potential. The GABAA receptor is a ligand-gated ion channel (Figure 3) formed by the hetero-oligomeric arrangement of five transmembrane spanning subunits from 16 different genes, a (1-6), p (1-3), g (1-3), 5, e, p, and 9. In most neurons, two a subunits, two b subunits, and one g subunit form the typical GABAA receptor. The 5, e, p, and 9 subunits have some reported selective functions but are not yet fully understood. The five subunits assemble to form an internal pore that is selectively permeable for anions. GABA binding to a specific site on each a subunit produces a conformational change in the complex that allows chloride ions to pass through the pore down a concentration gradient. BZs enhance the effect of GABA by binding to a distinct site at the interface of the a and g subunits increasing the affinity of GABA for its recognition site, acting as allosteric modulators of GABAA receptor function. Ligands that bind to the BZ site can enhance the effect of GABA (positive allosteric modulators, aka BZ agonists), reduce the effect of GABA (negative allosteric modulators, also known as BZ inverse agonists), or bind with no consequence for GABA, but compete with both positive and negative allosteric modulators (neutral allosteric modulators, also known as BZ antagonists). A continuum of allosteric effects is thus possible for BZ ligands. The degree of efficacy of BZ ligands (full or partial) is an important determinant of the pharmacological effect. The historical BZ anxiolytics, which also have anticonvulsant and muscle relaxant activities, e.g., diazepam (Figure 2b), are high efficacy positive allosteric modulators that produce a high degree of GABAA receptor enhancement, and the high efficacy negative allosteric modulators, e.g., the beta-carbolines, have the opposite effect, producing anxiolytic and convulsant effects by reducing GABAA receptor function.

Two moieties that were initially presumed to determine the activity of chlordiazepoxide, the methyl amine and N-oxide, could be removed without loss of biological activity. This structure-activity relationship (SAR) work led to the identification of the more potent BZ, diazepam. Acyclic analog 3 (amino ketone benzodiazepine precursor) is less active in [3H]-diazepam binding with IC50 values of greater than 1000 nM versus the cyclized analog 4, IC50 = 5.5 nM, indicating that the 7-membered ring maintains the key features in an optimal 3D arrangement (see Figure 2b).

Analogs have also been prepared where the lactam carbonyl has been incorporated into a 1,2,4-triazolyl heterocycle as seen in alprazolam and triazolam.85 Complete removal of the lactam carbonyl results in a significant loss (by two orders of magnitude) of biological activity. Beyond the two aromatic moieties there appears to be much flexibility with respect to substitution around the ring. Electron withdrawing groups on the aryl group are generally observed but polar substituents attached to the lactam amide group, illustrated in flurazepam, and polar hydroxyl or carboxy groups at the 3-position, present in oxazepam, temazepam and chlorazepate, hint at a significant flexibility in those regions (see Figure 4).




How To Win Your War Against Anxiety Disorders

How To Win Your War Against Anxiety Disorders

Tips And Tricks For Relieving Anxiety... Fast Everyone feels anxious sometimes. Whether work is getting to us or we're simply having hard time managing all that we have to do, we can feel overwhelmed and worried that we might not be able to manage it all. When these feelings hit, we don't have to suffer. By taking some simple steps, you can begin to create a calmer attitude, one that not only helps you feel better, but one that allows you the chance to make better decisions about what you need to do next.

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