BENZODIAZEPINE BINDING-SITE AGONISTS act not at a distinct receptor-effector entity (and cannot be cloned as independent receptors) but rather have a (normally positive) allosteric interaction at ‘modulatory’ binding-sites on GABAA receptors. GABAA receptors are of the heteromeric intrinsic-ion-channel superfamily, and these ligand-gated channels are permeant to chloride ions, so their effect on membrane excitability is normally inhibitory (see CHLORIDE-channel activators, gaba receptor agonists ). GABA (γ-aminobutyric acid) is thought to be the major inhibitory neurotransmitter within the CNS, and GABA receptors have a wide distribution within the body. The key feature of this benzodiazepines-GABAA interaction is a positive allosteric modification both of binding and action of GABA at its main ‘competitive site’ which is concerned with the gating of ion channel opening. Benzodiazepine agonists and GABA, mutually enhance binding at the GABAA receptors; the former increase the number of channels that are opened by a given concentration of GABA (rather than increasing the average open channel time or channel conductance). The molecular basis of these modulatory interactions of benzodiazepine and the GABAA receptor is reasonably well understood. A number of subunits of the GABAA receptors have been demonstrated, and their cDNA is structurally related to that of other receptors of the superfamily, and is a heteromeric pseudo-symmetrical transmembrane structure arranged in pentomers. A number of isoforms exist with different subunits (α, β, γ) which are products of different genes, as the resultant functional GABAA heterooligomeric receptors can be regarded as a family of receptors rather than a single receptor type. This diversity of receptor form, where subtypes are subject to tissue- and age-dependent transcriptional control, and tissue-dependent functional control at the protein level, raises the possibility of subtype-specific ligands. Which subunits, and what necessary amino acid residues within these subunits are involved in the actions of various classes of benzodiazepines, is increasingly being taken into account in practical drug design. It seems likely that there are different requirements for the action of archetypal benzodiazepines (e.g. diazepam) compared to some other agents (e.g. Ro 15-4513 and related imidazobenzodiazepine partial inverse agonists). Also, in operational binding terms, a distinction is made between diazepam-sensitive and diazepam-insensitive sites. A further type designated peripheral-type’, bears no relation to the usual types found in the CNS. It is located in the mitochondrial membrane, does not involve the GABAA receptor, but may regulate steroidogenesis both in the periphery and CNS (vide infra). It should also be noted that the existance of various endogenous benzodiazepine ligands have been noted; these include diazepam-binding inhibitor and its two major processing products octadecaneuropeptide (ODN) and triacontatetraneuropeptide (TTN).

Chemical classes other than benzodiazepines bind to, and have actions at the various benzodiazepine receptor sites. Notably, there are B-carbolines that have either agonist or inverse agonist actions, with a corresponding pharmacology similar to, or the opposite of typical benzodiazepines (e.g. anxiolytic or anxiogenic actions): see BENZODIAZEPINE RECEPTOR INVERSE AGONISTS.

Chemical families acting at benzodiazepine receptors. Since the synthesis in 1961 of the first member of the benzodiazepine group, chlordiazepoxide, many thousands have been synthesized, and about 20 are currently clinically available in the UK and USA. These include: alprazolam. bromazepam, chlordiazepoxide, clonazepam, diazepam, flunitrazepam, flurazepam, ketazolam, loprazolam, lorazepam, lormetazepam. nitrazepam, oxazepam and temazepam. All these drugs include the benzodiazepine ring fused to an aromatic ring, and there are four key substituent positions that determine pharmacological characteristics. These are used for numerous purposes, including as anxiolytics/sedatives/minor tranquillizers, hypnotics, anticonvulsants or antiepileptics, for preoperative use for the enhancement of the action of general anaesthetics, in dental sugery, and as centrally acting skeletal muscle relaxants and for a variety of other uses. Although these members may have different pharmacokinetic characteristics and some minor differences in pharmacological profile, they are in fact largely interchangeable.

Archetypal benzodiazepines contain a 5-aryl substituent ring and a 1,4-diazepine ring, so the term benzodiazepine drug has come to refer to 5-aryl-1,4-benzodiazepine. Various modifications of the ring system have yielded compounds with similar activity. These include 1,5-benzodiazepines (e.g. clobazam) and replacement of the fused benzene ring with heteroaromatic systems such as thieno (e.g. brotizolam). The substituents at the 1, 2 and 3 positions of the benzodiazepine ring can vary widely and may include imidazolo and triazolo rings fused at positions 1 and 2 (e.g. alprazolam, brotizolam, estazolam. midazolam and triazolam). Certain other benzodiazepine agonists developed are based on a 1,4-benzodiazepine ring, e.g. imidazenil, which is a new imidazobenzodiazepine with anxiolytic and anticonvulsant properties that acts as a partial agonist. Replacement of the 5-aryl substituent ring with a keto function and a methyl substituent at position 4 results in flumazenil, an important competitive antagonist (see BENZODIAZEPINE BINDING-SITE ANTAGONISTS). It should be noted that these competitive antagonists are thought to bind to similar subunit positions on the GABAA receptor as the archetypal benzodiazepine agonists. Some experimental agonists are based on a 2,3-benzodiazepine ring, also called homophthalazines (e.g. girisopam, nerisopam and tofisopam), which show strong anxiolytic .potency with reduced muscle relaxant and anticonvulsive activity, so differ from e.g. diazepam.

Non-benzodiazepines active at sites of the GABAA receptor not necessarily identical to those for benzodiazepines, have been sought in attempts to modify the pharmacological profile. These include a number of B-carbolines (i.e. containing an indole nucleus fused to a pyridine ring), that act as inverse agonists at flumazenil-sensitive benzodiazepine receptors, e.g. DMCM and β-CCM, and such agents have pro-convulsant, anxiogenic and possibly pro-cognition actions (see BENZODIAZEPINE RECEPTOR INVERSE AGONISTS). Other B-carbolines, e.g. abecarnil, have conventional agonist activity with anxiolytic and anticonvulsant properties, but with considerably reduced muscle relaxant effects in comparison with diazepam. Other types are based on imidazopyridines (e.g. zolpidem), imidazopyridines, imidazoquinolones and cyclopyrrolones (e.g. zopiclone). A number of examples of these with novel pharmacology have partial agonist actions, and may have components of their binding or action insensitive to the archetypal benzodiazepine antagonist flumazenil. The presence of diazepam-insensitive binding sites in the brain was referred to above. See also anticonvulsants; anxiolytic agents; gaba receptor antagonists; hypnotics; sedatives; skeletal muscle relaxants; tranquillizers.