Hello,

Diazepam binding inhibitor (DBI) protein, also known as acyl-CoA binding protein, is supposed to be the endogenous ligand of Benzodiazepine binding site of GABA-A receptor.

Christian, Catherine A., et al. "Endogenous positive allosteric modulation of GABA A receptors by diazepam binding inhibitor." Neuron 78.6 (2013): 1063-1074.

And, as it was mentioned above, GABA and Benzodiazepines have different binding sites. So they do not need to be structurally similar to act on GABA receptor.

These two paragraphs from the book: Medicinal Chemistry: A Molecular and

Biochemical Approach,  Third Edition,  may answer your question partly:

"It is generally accepted that endogenous or exogenous agents interact specifically with a receptor site on a specialized receptor molecule. Drug interaction with this site of binding, which has chemical recognition properties, may or may not trigger the sequence of biochemical events discussed above; therefore, one must distinguish carefully between sites of action (true receptors) and sites of binding (silent receptors or, occasionally, separate allosteric antagonist-binding sites)"

"Allosteric sites are at a distance from the agonist site and may even be on a different receptor protomer in the receptor–effector complex. Their occupation by allosteric inhibitors results in a conformational change that is propagated to the agonist site and changes its affinity. There is thus a mutual exclusion between the agonist and an allosteric antagonist. Moreover, classical pharmacological models cannot distinguish between competitive and allosteric inhibition. Allosteric effectors are not necessarily inhibitors. Just as in enzymology, some may activate whereas others deactivate one or another state of a receptor".

Hi, 

The natural agonist of GABA receptors is gamma-aminobutiric acid (gaba). Its site of binding differs from the one for benzodiazepines, which are uncompetitive agonists.This means that benzodiazepines have their own binding site and don't compete with gaba. So,  gaba and benzodiazepines differ in structure because they bind to different binding sites.

Hope that heps

Hello,

Diazepam binding inhibitor (DBI) protein, also known as acyl-CoA binding protein, is supposed to be the endogenous ligand of Benzodiazepine binding site of GABA-A receptor.

Christian, Catherine A., et al. "Endogenous positive allosteric modulation of GABA A receptors by diazepam binding inhibitor." Neuron 78.6 (2013): 1063-1074.

And, as it was mentioned above, GABA and Benzodiazepines have different binding sites. So they do not need to be structurally similar to act on GABA receptor.

Dear Ammar,

I agree with comments above. In summary there is no separate receptor that is specific just for benzodiazepines. So called "benzodiazepine receptors" are actually allosteric modulatory sites on "GABAA receptors", which are GABA-gated chloride channels. The endogenous ligand for the GABAA receptors is GABA (gamma-aminobutyric acid) made by inhibitory neurons (usually interneurons).

Best wishes, Refik

Absolutely agree with the above; Benzos bind to allosteric regions of the GABA receptors, and potentiate the effects of GABA on them; i.e. enhance the Cl- flux  mediating a reduction in membrane excitatory polarisation potential. Thus there is no truly specific 'benzodiazepine receptor' other than  allosteric sites. As far as I am aware (but I may be wrong) that bezodiazepines do not necessarily have an effect on their own. They modulate/potentiate the effects of GABA signalling at the canonical binding site by causing a structural change in the receptor allowing the Cl ion pore to open more readily.. hence, a greater Cl flux... thus as pointed out there is  no need for structural similarities between the ligands as they bind the same protein at different sits.

Good question and well done replies, thanks to all! In a recent past in Katsung`s book some Authors have termed it as omega receptor, or site, for calling the binding site for the allosteric site to the BDZ`s, other than the GABA sites.

Just for knowledge!

Regards,

Wilson

• At first, there are two types of benzodiazepines receptors were discovered in body , the first is the central benzodiazepine receptor (part of GABA-A Cl-ion channel complex)  that mediate an inhibitory effects of brain neurons (protecting neurons from excess excitability) and there are endogenous brain substances were discovered to be the natural agonist or modulator of these receptor ; called benzodiazepine-like compounds (termed endozepines) very similar to diazepam (prototype agonist of central  benzodiazepine receptor.
• The second type of BZDs receptors, is called  “ peripheral benzodiazepine receptors” (PBRs) , have been identified in mitochondria of neuronal and non-neuronal cells as adrenal cortex cells exerting anti- inflammatory properties via stimulating synthesis of corticosterone , plus other cells of  immune system , such as monocytes, neutrophils, macro phages , may modulate peripheral immunological functions; and also it was reported from clinical and experimental studies that diazepam and endogenous endozepines also acting on these PBRs as agonist

The discoveries of endogenous ligands for opiate receptors (enkepkalins, etc) and cannabinoid receptors (anandamide), motivated a search for endogenous benzodiazepine receptor ligands ("endozepines"). After years of research there is still no clear candidate endozepine. We have to accept the inability to answer every question. Perhaps the discovery is around the corner, but perhaps there are no endozpines altogether.

Review: Farzampour Z, Reimer RJ, Huguenard J. Endozepines. Adv Pharmacol. 2015;72:147-64. doi: 10.1016/bs.apha.2014.10.005.