Nicotinic α4β2 program for treatment of cognitive impairment

Nicotinic acetylcholine receptors (nAChR) constitute a class of pentameric ligand-gated ion channels broadly expressed in the mammalian brain. They are activated by acetylcholine under physiological conditions and the role of nicotinic receptors primarily seems to be positive modulation of release of other neurotransmitters, e.g. glutamate and GABA. The α4β2 nAChR subtype accounts for 70-80% of all brain nAChRs and consequently represents the predominant nAChR of the mammalian brain.

In certain pathological conditions, such as Alzheimer’s disease and schizophrenia, cholinergic neurotransmission and expression of nicotinic receptors (notably α4β2) are reduced. This finding is believed to contribute to the cognitive disturbances inherent to these disorders. It is widely recognised that activation of nicotinic receptors induces enhancement of cognitive function in laboratory animals as well as in humans. Indeed, numerous studies have demonstrated cognitive augmentation by nicotine (i.e. from patches, gums or cigarette smoking) in healthy volunteers and patients suffering from Alzheimer’s disease, ADHD or schizophrenia. However, nicotine itself is poorly suited for use as a therapeutic drug due to the many adverse events caused by the non-selective nature of the compound.

Saniona has explored a unique approach by identifying positive allosteric modulators (PAMs) of the a4b2 nAChRs. Contrary to traditional agonists, PAMs act through augmentation of endogenous cholinergic neurotransmission and do not desensitize the receptors. Further, such compounds may be advantageous over direct agonists in that the function of nicotinic receptors are only affected when the endogenous ligand, acetylcholine, is released by naturally occurring synaptic transmission. PAM substances can therefore increase the amplitude of endogenous cholinergic transmission and consequently preserve its temporal and spatial resolution that cannot be accomplished by an agonist.

Our α4β2 PAMs have shown excellent selectivity against major physiologically relevant nAChR subtypes, good brain exposure after oral dosing and marked effect in alleviating cognitive dysfunction across several rodent cognition models. Collectively, these data suggest that α4β2 nAChR PAMs could serve as a new treatment strategy in disorders characterized by cognitive impairment such as Alzheimer's disease, schizophrenia and ADHD.

The program is in the drug discovery phase.