A new focus on the central cholinergic system

CHDR has longstanding experience with agents that act on the acetylcholine system in the brain. Cholinergic drugs such as donepezil, a cholinesterase inhibitor, are being used to treat patients with Alzheimer's disease. However, these compounds also cause adverse effects, caused by the peripheral actions of acetylcholine on the autonomic nervous system. But now, promising new treatments with cholinergics and anticholinergics are being developed, thanks to innovative solutions and compounds that are more receptor subtype selective, ‘We have recently investigated some of these compounds and are now working on validating a challenge model for profiling drug effects of cholinergic compound’ says Dr Philip Kremer, research director of Neurology.

An example of an innovative solution to the peripheral side effects of cholinergics is the combination of xanomeline and trospium for the treatment of patients with schizophrenia under the brand name Cobenfy. Xanomeline, a selective muscarinic (M1 and M4) agonist, is the first compound effective against hallucinations which does not act directly on dopamine neurons. Trospium is a peripherally acting anticholinergic that counteracts the peripheral side effects of xanomeline. Kremer: ‘Centrally acting muscarinic agonists that are more selective to the M1 receptor may have even fewer intrinsic side effects and could perhaps be used in the treatment of dementia’.

Inhibition of M4 muscarinic receptors in the striatum can potentially have a beneficial effect in patients with Parkinson's disease (PD). Classic cholinergic drugs used in the treatment of PD such as trihexyphenidyl and biperiden are less specific muscarinic receptor antagonists. More selective M4 inhibitors are currently being developed as treatments for PD.

Kremer and his team are working on a challenge model to measure cholinergic or anticholinergic actions of new compounds. 'We will be using donepezil as a cholinergic agent and measure how we can counteract the anticholinergic effects of the drug biperiden. By properly quantifying the action of those two agents, we aim to develop and validate a model that will allow us to profile the action of a novel cholinergic compound in healthy study participants. With this model, we hope to contribute to the early drug development of new treatments and help increase the quality of life of patients with debilitating diseases such as PD and Alzheimer's.'