Partial agonists of the benzodiazepine receptor: from animal data to results in patients.
The BZR is an allosteric modulatory site of the GABAA receptor, which is unique insofar as it mediates both a positive (facilitatory) and a negative (inhibitory) modulation of the GABA-mediated gating of the chloride channel. Ligands acting as positive modulators are called BZR agonists; ligands producing negative modulation, inverse BZR agonists. The effects of both classes of ligands are blocked by antagonists. A large number of compounds belonging to these three groups of ligands are known. Concepts are presented here that could explain the modulatory function of the BZR, and a number of factors are proposed to determine the pharmacological and therapeutic profile of BZR ligands: intrinsic efficacy at the BZR, density of GABAA-BZR on neurons, functional reserve in GABAA-BZRs, the intensity of the GABAergic input to a neuron, and the excitatory neuronal state. The effect of these factors on the pharmacology of full agonists, partial agonists, antagonists, partial inverse agonists, and inverse agonists is illustrated.
Haefely
W
W
Pharmaceutical Research Department, F. Hoffman-La Roche & Co. Ltd., Basel, Switzerland.
D000345:Affinity Labels; D000495:Allosteric Site; D000818:Animals; D001386:Azides / Q000494:pharmacology; D001569:Benzodiazepines / Q000494:pharmacology; D001570:Benzodiazepinones / Q000494:pharmacology; D002707:Chlordiazepoxide / Q000494:pharmacology; D002712:Chlorides / Q000378:metabolism*; D002998:Clonazepam / Q000494:pharmacology; D003975:Diazepam / Q000494:pharmacology; D004347:Drug Interactions; D000431:Ethanol / Q000037:antagonists & inhibitors / Q000494:pharmacology; D005442:Flumazenil / Q000494:pharmacology; D005479:Flurazepam / Q000494:pharmacology; D006801:Humans; D007473:Ion Channels / Q000378:metabolism*; D008024:Ligands; D008959:Models, Neurological; D009474:Neurons / Q000187:drug effects; D011963:Receptors, GABA-A / Q000032:analysis / Q000187:drug effects*
D000345:Affinity Labels; D001386:Azides; D001570:Benzodiazepinones; D002712:Chlorides; D007473:Ion Channels; D008024:Ligands; D011963:Receptors, GABA-A; D001569:Benzodiazepines; D000431:Ethanol; D005442:Flumazenil; D002998:Clonazepam; D002707:Chlordiazepoxide; C042957:Ro 15-4513; D005479:Flurazepam; C054626:bretazenil; D003975:Diazepam