Mithridion, Inc. - Breaking new ground in drugs for Alzheimer's disease and schizophrenia

Technology Platform

Mithridion's Subtype Selective Muscarinic Agonist Platform

Clinical Experience with Muscarinic Agonists

Technology Platform

Muscarinic Agonists

Mithridion is an emerging leader in the development of receptor-subtype selective muscarinic agonists.

The Therapeutic Promise of Muscarinic Agonists
M1-type muscarinic receptors in the brain, which may be activated by the neurotransmitter acetylcholine, are important for memory and cognition. It has long been known that blocking muscarinic receptors, with receptor antagonist drugs, such as scoplolamine, causes memory and cognition impairment in laboratory animal models, and in humans. It has also been shown in laboratory animals and humans, that activating brain muscarinic receptors (with muscarinic agonists) can improve memory band cognition.

More interesting yet, muscarinic agonists have the potential to slow down or halt the disease processes in Alzheimer’s disease via multiple modes of action:

Decrease the activity of β-secretase, reducing the production of the Aβ, the main constituent of amyloid plaques, and a major cause of neuronal dysfunction and neuronal death in AD
Increase the activity of α-secretase, reducing the production of Aβ, and increasing the production of sAPPα, which may protect neurons
Reduce the phosphorylation of Tau, another protein thought to be involved in neuron disfunction and death
Reduce the programmed death of neurons (apoptosis)

Muscarinic Receptors in Alzheimer's Disease (AD)
Several lines of research show that in key areas of the brains of patients with AD, there are less neurons producing acetylcholine (cholinergic neurons), most likely due to the killing these neurons by the neurotoxic peptide Aβ. This appears to be an important cause of memory loss, since loss of such cholinergic neurons in laboratory animals, regardless of how it is caused (transgenic gene knockout, lesions caused by administering toxins, or muscarinic antagonists in normal animals), impairs cognitive function and memory.

Muscarinic agonist drugs may overcome this deficiency, since there is not a deficit of the postsynaptic neurons that carry M1-type muscarinic receptors and respond to acetylcholine. In other words, the drug replaces the lost acetylcholine. The drug should be selective in its action on the M1-type muscarinic receptor, and not activate the other subtypes, especially M2 and M3, to avoid unwanted side effects:

Activation of M2 receptors slows down the heart and may cause tremor
Activation of M3 receptors causes sweating, salivation, tear production, and numerous gastrointestinal tract effects, including diarrhea

Role of Muscarinic Receptors in Schizophrenia
Several lines of research suggest that the muscarinic cholinergic system plays an important role in the pathogenesis of schizophrenia, and muscarinic agonists may be useful in the treatment of schizophrenia (reviewed by Raedel, Bymaster and others “Towards a muscarinic hypothesis of schizophrenia”, Mol Psych (2007), 12, 232-246).