Benzodiazepine receptor ligands

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... 

Braestrup C, Nielsen M, HonoreT, etal Benzodiazepine receptor ligands with positive and negative efficacy. Neuropharmacology 22 1451—1457, 1983... 

Reynaud M, Petit G, Potard D, et al Six deaths linked to concomitant use of buprenor-phine and benzodiazepines. Addiction 93 1383-1392, 1998 Richards JG, Martin JR Binding profiles and physical dependence liabilities of selected benzodiazepine receptor ligands. Brain Res Bull 43 381-387, 1998... 

The term benzodiazepine refers to a specific chemical structure. Numerous benzodiazepine-receptor ligands exist which have different structures. These include the jS-carbolines (e.g. methyl-6,7-dimethoxy-4-ethyl-jS-carboline 3-carboxylate DMCM), triazolopyridazines (e.g. CL 218872), imidazopyridines (e.g. zolpidem), and pyrazolo-quinolinones (e.g. CGS 8216). In experimental animals these compounds produce... 

THE QUEST FOR THE ENDOGENOUS BENZODIAZEPINE RECEPTOR LIGAND ( ENDOZEPINES )... 

Dysfunction of the GABAa receptor complex such that the effects of all benzodiazepine receptor ligands are shifted in the direction of inverse agonism. In this case, fiumazenil (which normally has zero efficacy) should induce anxiety in anxious patients but have no effects in healthy subjects because they have normal receptors. 

Kwok MH, Huen MSY, Wang HY, et al. Anxiolytic effect of wogonin, a benzodiazepine receptor ligand isolated from Scutellaria baicalensis Georgi. Biochem Pharmacol 2002 64 1415-1424. 

Viola H, Wasowski C, Levi de Stein M, et al. Apigenin, a component of Matricaria recutita flowers, is a central benzodiazepine receptors-ligand with anxiolytic effects. Planta Med 1995 61 213-216. 

Erker and Trinkl synthesized the tricycles 177 as novel GABA-A/benzodiazepine receptor ligands via synthesis of enol phosphates such as 175 and reaction with isocyanides 176 (Scheme 13) <2001H1963>. 

Rothstein JD Benzodiazepine-receptor ligands and hepatic encephalopathy A causal relationship Hepatology 1994 19 248-250. 

Yurdaydin C, Walsh TJ, Howard DE, Ha J, Li Y, Jones EA, Basile AS Gut bacteria provide precursors of benzodiazepine receptor ligands in a rat model of hepatic encephalopathy. Brain Res 1995 679 42-48. 

Basile AS, Harrison PM, Hughes RD, Gu ZQ, Pannell L, McKinney A, Jones EA, Williams R Relationship between plasma benzodiazepine receptor ligand concentrations and severity of hepatic encephalopathy. Hepatology 1994 19 112-121. 

Medina JH, Viola H, Wolfman C, Marder M, Wasowski C, Calvo D, Paladini AC. (1997). Overview— flavonoids a new family of benzodiazepine receptor ligands. Neurochem Res. 22(4) 419-25. Menghini A, Mancini LA. (1988). TLC determination of flavonoid accumulation in clonal populations of Passiflora incarnata L. Pharmacol Res Commun. 20(suppl 5) 113-16. 

Wolfman C, Viola FI, Paladini A, Dajas F, Medina JFI. (1994). Possible anxiolytic effects of chrysin, a central benzodiazepine receptor ligand isolated from Passiflora coerulea. Pharmacol Biochem Behav. 47(1) 1-4. 

Substances with a neuromodulatory effect on brain neurotransmitters by direct actions of specific receptors that modify the actions of the transmitters listed include prostaglandins, adenosine, enkephalins, substance P, cholecystokinin, endorphins, endogenous benzodiazepine receptor ligands, and possibly histamine. CNS, central nervous system. NMDA, N-methyl-D-aspartate. Strych, strychnine. 

Gourdeau H, McAlpine JB, Ranger M, Simard B, Berger F, Beaudry F, Falardeau P. (2008) Identification, characterization and potent antitumor activity of ECO-4601, a novel peripheral benzodiazepine receptor ligand. Cancer Chemother Pharmacol 61 911-921. 

Cinone, N., Holtje, H.-D., Carotti, A. Development of a Unique 3D Interaction Model of Endogenous and Synthetic Peripheral Benzodiazepine Receptor Ligands. /. Comput.-Aided Mol. Des. 2000, 14, 753-768. 

Until about 1980, it was widely accepted that the benzodiazepine structure was a prerequisite for the anxiolytic profile and for the recognition of and binding to the benzodiazepine receptor. More recently, however, a chemically unrelated drug, the cyclopyrrolone zopiclone, has been shown to be a useful sedative hypnotic with a benzodiazepine-like profile. Other chemical classes of drugs that are also structurally dissimilar to the benzodiazepines (e.g. triazolopyridazines) have also been developed and shown to have anxiolytic activity in man these non-benzodiazepines also act via the benzodiazepine receptor. Thus the term "benzodiazepine receptor ligand" has been introduced to describe all drugs, irrespective of their chemical structure, that act on benzodiazepine receptors and thereby modulate inhibitory transmission in the brain. 

Figure 9.12. Properties of the various types of benzodiazepine receptor ligands.

In CONCLUSION, evidence has been presented to show that the benzodiazepines produce their variety of pharmacological effects by activating specific receptors that form part of the main inhibitory neurotransmitter receptor system, the GABA receptor, in the mammalian brain. Different classes of benzodiazepine receptor ligands have been developed which can alleviate anxiety or produce anxiety according to the fine structural changes that occur when the drugs interact with the benzodiazepine receptor. 

Barbituric acid derivatives, history and applications 88PHA827. Benzodiazepine receptor ligands as drugs 89FES345. Coumarine-based antioxidants 88KFZ1438. 

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