Anavex 2-73 in Amyloid and Tau Pathology - Drug Discovery and Development

Anavex Life Sciences Corp. conducted a study entitled, “The novel aminotetrahydrofuran derivative Anavex 2-73 attenuated GSK-3beta and Tau hyperphosphorylation in a nontransgenic Alzheimer’s disease model in mice.”

Anavex 2-73 is a mixed sigma-1 agonist, muscarinic-1 agonist and a muscarinic-2 and 3 antagonist, which has shown neuroprotection in animal models. Researchers found that Anavex 2-73 dose-dependently prevents memory deficits and also appears to increase levels of Akt, a serine/threonine protein kinase, and decrease levels of GSK-3beta, thereby decreasing tau hyperphosphorylation.

Researchers injected oligomeric amyloid 25-35 fragments into the brain of mice in order to mimic Alzheimer’s according to a well-established nontransgenic animal model in rodents. Hallmark indicators of AD inside (intracellular) and outside (extracellular) cells can be induced by this model. The intracellular deposits are composed of tau protein. Tau protein, once abnormally phosphorylated and hyperphosphorylated, can clump together within neurons, creating tangles referred to as neurofibrillary tangles (NFTs), which are associated with poorly functioning neurons and cell death. Extracellular deposition of amyloid beta proteins leads to amyloid plaque. In AD, both mechanisms may be at play and can lead to acceleration of each other.

The study tested the hypothesis that drugs which may act as neuroprotectants (an effect that has been previously described for Anavex 2-73) can also impact tau phosphorylation generated through this amyloid 25-35 injection model. It is thought that tau phosphorylation, hyperphosphorylation and ultimately NFTs may be triggered via certain key enzymes, such as an increase in glycogen synthase kinase – 3 beta (GSK-3beta).

The researchers experimented with Anavex 2-73, the first of a new class, the aminotetrahydrofurans, which are being developed by Anavex as lead small molecules for AD.

“It may be that Akt increase and GSK-3beta decrease is a protective mechanism in AD and is restored by mixed sigma-1 and muscarinic agents such as Anavex 2-73,” says Tangui Maurice, MD, PhD, CNRS research director, Team II Endogenous Neuroprotection in Neurodegenerative Diseases INSERM, University of Montpellier. “For the very first time, these data show these mixed sigma and muscarinic agents, such as ANAVEX 2-73, block both amyloid-related toxicity and tau protein-related pathology.”

Release Date: July 25, 2011
Source: Anavex Life Sciences Corp.