Mechanism of action: Nicotinic acetylcholine receptor alpha 7 (α7 nAChR) agonist

Preclinical pharmacology

AZD0328 is a stereo-selective, potent, full agonist of the human α7 nAChR (binding IC50 of 3nM; activation of whole cell current IC50 of 2.9μM; intrinsic activity = 101% compared with acetylcholine). It is ~20-fold selective to the α1β1γδ nAChR, 1000-fold selective to other nicotinic receptors and a panel of other targets (inhibition of radioligand binding), and is equipotent with the structurally related serotonin 5HT3 receptor (2μM). Oral administration of AZD0328 significantly improves operant conditioning and long-term potentiation in rats. In Rhesus monkeys, spatial working memory is enhanced at doses above 0.001mg/kg (plasma compound levels of ~0.2 x whole cell current IC50).

Safety and tolerability

In single and multiple ascending dose clinical studies, where AZD0328 was studied at up to 2mg and 1.35mg (for 13 days), respectively, the most common adverse events reported were nausea, facial flushing and gastrointestinal disturbances; nausea limited clinical tolerability at doses ≥1.35mg. In a Phase 2a study, AZD0328 at doses of up to 0.675mg once daily for 14 days, did not show any major safety or tolerability concerns in subjects with schizophrenia other than a dose-related incidence of nausea.  The MTD for multiple dose administration in the context of the original indication was determined to be 1mg.

Preclinical studies of up to 6 months duration have been performed.

Clinical pharmacology

In a 14 day Phase 2a clinical study in patients with schizophrenia, concurrently taking an additional anti-psychotic drug, AZD0328 (0.00093 to 0.675mg; plasma levels ~5 x IC50 at 0.675mg dose), did not show a statistically significant improvement in cognition, or other secondary endpoints.

Suitable for and exclusions

The reproductive toxicology package indicates a risk of foetal toxicity. The inclusion of women of child-bearing potential would need to be assessed for any proposal based on the risk benefit and the use of appropriate highly effective contraception.

AZD0328 is renally cleared and, therefore, future studies will require an assessment of the risk benefit for subjects with renal impairment.

Additional Information

Clinical trials for this compound

See all of the clinical trials currently associated with this compound:

Publications for this compound

Find out more about this compound by reading related publications:

Selective α7 nicotinic receptor activation by AZD0328 enhances cortical dopamine release and improves learning and attentional processes

Gene information from the NCBi

This compound works on the following genes: