From what I've studied on receptor kinetics, ultimately combining with an alpha-7 nicontinic positive allosteric modulator will reduce receptor desensitization, and provides a viable long term strategy.
The magnitude of desensitization remains to be seen though. EVP-6124 is a partial agonist, where as nicotine is IIRC a full agonist. Full agonists generally cause much greater receptor desensitization than partial agonists.
Hey 3AlarmLampscooter, glad to have you on board. After doing more research on EVP-, I also agree that receptor desensitization may not be an issue, perhaps only at higher doses which appear to have negative implications on memory in rat studies anyway. So when you talk about PAM's for Alpha-7 agonist potentiation, you mean something like Nefiracetam? From my limited knowledge I assume the other racetam's mostly have AMPA allosteric modulation, though this property could also synergize with EVP-.
Here is some quotes taken from the hallmark study that are of relevant interest to alpha-7 nicotinic receptor desensitization and how it is suggest there is another mechanism of action besides a7 nAChR affinity.
Based on the pharmacokinetic data, estimation of the maximum effective brain concentration in the ORT (object recognition test) after a dose of 0.3 mg/kg, p.o. was about 2 nM (total concentration of EVP-6124) and less than 1 nM free drug. Thus, in spite of the high affinity of EVP-6124 for a7 nAChRs, a concentration lower than 3 nM was clearly insufficient to activate the receptor in in vitro studies, suggesting an alternative mechanism of action...
...sustained exposure to a concentration of EVP-6124 below 1 nM potentiated the ACh-evoked current. Increasing the EVP-6124 concentration to 3 nM or above, caused a marked reduction of the ACh-evoked current that was attributable to receptor desensitization......The pro-cognitive effects after EVP-6124 administration appear to have occurred at brain concentrations below those that caused desensitization.
...the presence of a low concentration of EVP-6124, in the sub-nanomolar range increased the ACh-evoked current by a factor of two or more
...Although different mechanisms can be postulated to account for the observed potentiation, the simplest and most probable model considers the co-agonistic behavior of EVP-6124 and ACh at a7
nAChRs.
So it then goes on to explain what they mean by co-agonism and why it leads to an improved side effect profile over full agonism. I found it rather interesting that nAChR's have two binding sites for ligands and there must be two ligands bounded to the receptor to trigger channel opening and an inward current.
It appears to be more favourable to increase the efficiency of EVP- with the addition of an acetylcholinesterase inhibitor (rather than increasing dosage of EVP-) due to the increased potentiation from ACh occupying a binding site. This approach avoids receptor desensitization associated with higher doses of EVP-.
Source:-
http://aimday.se/wp-...oad/EVP6124.pdf
Edited by Dazzcat, 04 February 2014 - 10:54 PM.
