Anavex Life Sciences Corp (AVXL)

[orveko_inc]

Excellent write ups.

One possible correction: I think you mixed up ANAVEX 2-73 and ANAVEX 3-71 with regard to their muscarinic receptor affinities.

So, how does A2-73, which is an agonist of muscarinic (M1-2-3-4) receptors, namely M1—the most common muscarinic receptor in the brain, important in motor control, sleep-wake cycle regulation, memory, and attention—presume to do any better than Donepezil [10]? I can only speculate. Given that the M1 receptor is coupled to a 7-transmembrane G-protein, activating it directly must have more longevity downstream than simply making more acetylcholine available in the synaptic cleft, but the literature is quite clear that M1 activation alone has promise in the field of Alzheimer’s therapy. Coupled with the hypothesis in early A2-73 literature that suggests a possible synergistic effect with S1/M1 receptor agonism, and the possibilities, in my opinion, favorably expand [11].

In the above section, you cited a work by Dr. Abraham Fisher, the inventor of ANAVEX 3-71 (formerly AF710B). A3-71 is indeed an agonist of the M1 receptor, but A2-73 is more mixed. A2-73 does seem to be an agonist of M1 but it is an antagonist of M2 and M3 (unsure about M4). This antagonism of the M2 and M3 receptors is seemingly what makes it such a good match for donepezil.

This is from Dr. Alexandre Vamvakides (inventor of A2-73) in his original Greek patent application for what is now ANAVEX PLUS (A2-73 + donepezil):

Indeed, all these aminotetrahydrofurans are antagonists of the M2 and M3 muscarinic receptors which originate the cholinergic side effects of Rivastigmine, Galantamine and Donepezil.

More importantly, the increase of acetylcholine on presynaptic muscarinic M2 auto-receptors, induced by the IACEases (Rivastigmine, Galantamine or Donepezil) is deleterious for the cholinergic neurons and for all the neuronal systems modulated by the extrasynaptic M2 receptors (especially in AD and in ageing, where these M2 auto-receptors are hyper-activated by neurotoxins and soluble amyloids) and could be the most important factor explaining the absence of the therapeutic effects of these drugs on the evolution of AD and also their weak effects against the AD symptoms. Indeed the high concentrations of acetylcholine, induced by the IACEases Galantamine, Rivastigmine and Donepezil, hyper-stimulated the M2 auto-receptors which exerced high inhibition of the released acetylcholine and severe hypo-activity of the presynaptic cholinergic neurons therefore inducing, in a first phase, the diminution of the cholinergic effect on Ml and nicotinic receptors (insufficient symptomatic benefit) and, in a second phase, degeneration of hypoactive cholinergic neurons (absence of therapeutic effects on the evolution of AD and, possibly, even worsening)

https://patentscope.wipo.int/search/en/detail.jsf?docId=WO2014155138&recNum=1&maxRec=&office=&prevFilter=&sortOption=&queryString=&tab=PCTDescription

Basically, A2-73's agonism of sigma-1 and M1 receptors may work to alter the progression of AD, while its antagonism of the M2 and M3 receptors may work to improve the affects of donepezil on the symptoms of the disease.