AZD0328
Preclinical pharmacology
AZD0328 is a potent, stereo-selective, full agonist of the human α7 nAChR.
| Binding (IC50) | 3nM |
| Activation of whole cell current | 2.9µM |
| Intrinsic activity (vs acetylcholine) | 101% |
Radioligand binding assays showed that AZD0328 has ~20-fold greater selectivity to the α1β1γδ nAChR, 1000-fold greater selectivity to other nicotinic receptors and a panel of other targets. Equipotency was observed with the structurally related serotonin 5HT3 receptor (2μM).
In rats, AZD0328 significantly improved operant conditioning and long-term potentiation in rats following oral administration. In Rhesus monkeys, spatial working memory was enhanced at doses above 0.001mg/kg (plasma compound levels of ~0.2 x whole cell current IC50).
Safety and tolerability
In SAD and MAD clinical studies, AZD0328 was studied at up to 2mg and 1.35mg (for 13 days) respectively. The most common adverse events reported were facial flushing, gastrointestinal disturbances and nausea; the latter 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, reported no 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 safety 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 did not show a statistically significant improvement in cognition, or any other secondary endpoints (Dosing: 0.00093 to 0.675mg; plasma levels ~5 x IC50 at 0.675mg dose).
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
Mechanism of Action
Nicotinic acetylcholine receptor alpha 7 (α7 nAChR) agonist
Original Therapeutic Area
Neuroscience
CNS Penetrant
Yes
Route of administration
Oral
Modality
Small Molecule
Additional Information
1. Sydserff S., et al. (2009).
Selective α7 nicotinic receptor activation by AZD0328 enhances cortical dopamine release and improves learning and attentional processes. Biochemical Pharmacology, 78 (7) 2009, 880-888. DOI: 10.1016/j.bcp.2009.07.005.