Replies to post #176002 on Anavex Life Sciences Corp (AVXL)

[XenaLives]

Possibly working in parallel with 2-73 S1 receptors.

The question that I'd really like answered is will 2-73 help the brain remove plaque deposits without Donepezil and it's potentially harmful side effects?

[Investor2014]

“Can both bind concurrently at different receptor locations?”

That would seem a logical possibility also considering that Anavex PLUS is including low dose < 5mg of Donepezil presumably more for its acetylcholinesterase inhibitor than its affinity for S1R.

[OFP]

As I understand it Sigma1 one agonists competes with any other in a winner take all fashion. Can both bind concurrently at different receptor locations?

My understanding is that there is one orthosteric binding site known and that the binding assays used to determine affinities would have assessed that known site only. IF that is true then it would be winner take all for a given receptor at a given point in time. That being said (and based on fuzzy pharmacology recall), over time and over huge numbers of available receptors the probability of binding at a given receptor at a given point in time would be determined by determined by relative binding affinities and disassociation constants. Specific probability determination is beyond my current ability without some remedial work...maybe someone else can describe more precisely.

For those more firmly rooted in pharmacology this would be a very basic issue and one I would expect AVXL would have answered for themselves very early on.

[Steady_T]

The answer to your question is that binding and activation are not the same thing.

Not every ligand that binds to a receptor also activates that receptor. The following classes of ligands exist:

(Full) agonists are able to activate the receptor and result in a strong biological response. The natural endogenous ligand with the greatest efficacy for a given receptor is by definition a full agonist (100% efficacy).
Partial agonists do not activate receptors with maximal efficacy, even with maximal binding, causing partial responses compared to those of full agonists (efficacy between 0 and 100%).
Antagonists bind to receptors but do not activate them. This results in a receptor blockade, inhibiting the binding of agonists and inverse agonists. Receptor antagonists can be competitive (or reversible), and compete with the agonist for the receptor, or they can be irreversible antagonists that form covalent bonds (or extremely high affinity non-covalent bonds) with the receptor and completely block it. The proton pump inhibitor omeprazole is an example of an irreversible antagonist. The effects of irreversible antagonism can only be reversed by synthesis of new receptors.
Inverse agonists reduce the activity of receptors by inhibiting their constitutive activity (negative efficacy).
Allosteric modulators: They do not bind to the agonist-binding site of the receptor but instead on specific allosteric binding sites, through which they modify the effect of the agonist. For example, benzodiazepines (BZDs) bind to the BZD site on the GABAA receptor and potentiate the effect of endogenous GABA.