Replies to post #141267 on Anavex Life Sciences Corp (AVXL)

[XenaLives]

SSRI's - cross those off the list....

Many people can't take them (including myself) and apparently they don't work for their approved purpose.

https://www.psychologytoday.com/blog/obsessively-yours/201001/five-reasons-not-take-ssris

[Mikesc]

Thanks F1ash....

[OFP]

The strongly bound compound could be a partial agonist and the weakly binding compound could be a full agonist, or vice versa. So, the 5 nM compound is stronger on a weight basis, but may not have stronger effects at equivalent doses.”

This point is made repeatedly here...usually in less scientific terms. Factors that shed some light include the mouse data showing the S1R effects as greater than or equal to 2-73 thereby suggesting that the agonism is as least as great (though not fully defined). Also, if they use the same binding site the higher affinity DZP will block 2-73 from even binding to the S1R for those that are occupied.

[ExtremelyBullishZig]

You didn't like the names I picked out? John, Donald, or Susan?

[XenaLives]

Another red herring argument...

Just because there are other S-1 agonists out there does not detract from the fact that Anavex 2-73 is clinically more promising than any of these.

“Fluvoxamine (SSRI) 17.0
Sertraline (SSRI) 31.6
Fluoxetine (SSRI) 191.2
Escitalopram (SSRI) 288.3
Citalopram (SSRI) 403.8
Paroxetine (SSRI) 2041
Duoxetine (SNRI) 3533
Venlafaxine (SNRI) >10,000 Milnacipran (SNRI) >10,000 Mirtazapine (NaSSA) >10,000

Activation of sigma-1 receptor chaperone in the treatment of neuropsychiatric diseases and its clinical implication

https://ac.els-cdn.com/S1347861314000176/1-s2.0-S1347861314000176-main.pdf?_tid=188f1d70-1319-11e8-a85c-00000aab0f01&acdnat=1518786094_9ee528a53583943bed94a71e95778fce

· Donepezil (Aricept®) is a potent acetylcholinesterase inhibitor that is used in treating Alzheimer's disease. The compound is also a potent sigma-1 receptor ligand with an affinity of 14.6 nM

https://www.ncbi.nlm.nih.gov/pmc/articles/PMC2785038/
The receptor binding profile of Anavex 2-73 is:
Ki of 860 nM for sigma 1 receptor

https://investorshub.advfn.com/boards/read_msg.aspx?message_id=118560971

Probably a decent idea to read the above link imho.

“Usually, the *lower* the Ki number, the more affinity; which is measured by the displacement of another (radiolabled for example) exogenous ligand.”

“For binding affinity people generally are referring to either the dissociation constant (the Kd value) or the association constant, Ka, which has no units. For your question why does it seem backwards, well Ka = 1/Kd. If units are given it is usually referring to Kd, the equilibrium dissociation constant (equilibrium referring to the binding and unbinding reactions).

Ki, or the inhibition constant, has to do with competitive binding assays and relates the ligand with the amount of competitor that displaces half of it (the IC50). “

http://www.bluelight.org/vb/threads/774430-Receptor-Binding-affinity-meaning-and-units

“The affinity is measured by the concentration required to get 50% binding. If it is 5 nM for one compared to 50 uM for another, then it takes 10,000 times more ligand to get the same binding for the 50 uM compound as the 5 nM compound. However, the binding tells you nothing about the efficacy. The strongly bound compound could be a partial agonist and the weakly binding compound could be a full agonist, or vice versa. So, the 5 nM compound is stronger on a weight basis, but may not have stronger effects at equivalent doses.”

Serotonin syndrome is a real danger with the SSRI's listed. The medical community is starting to back off on them for psychiatric and neuropsychiatric use.

https://www.mayoclinic.org/diseases-conditions/serotonin-syndrome/symptoms-causes/syc-20354758