Mechanism of action: Metabotropic glutamate receptor 2 (mGluR2) positive allosteric modulator
AZD8529 is a potent (binding Ki of 16 nM) and specific PAM for mGluR2. It potentiates the effects of glutamate on mGluR2 with an EC50 of 195nM (max glutamate EC50 shift of 7.4-fold) and Emaxof 110% (max potentiation of Emax by 1.3-fold). Specific activity as an agonist, antagonist, or PAM was tested for recombinantly expressed mGluR1, 3, 4, 5, 7, and 8 in HEK cells. AZD8529 produced only weak PAM for mGluR5 (EC50 of 3.9μM) and antagonism for mGluR8 (IC50 of 23μM). Selectivity was evaluated at 10μM in 161 receptor, enzyme or ion channel assays with only modest activity found at 9 targets. AZD8529 exhibits concentration-dependent reductions in psychomotor activity and neural firing in rodent models. AZD8529 alone (57.8 to 115.7mg/kg, sc) or in combination with an atypical antipsychotic (5.8mg/kg, sc) reversed the hyper-locomotion induced by administration of phencyclidine in a murine model of schizophrenia.
Safety and tolerability
AZD8529 has been administered at single doses of up to 310mg and repeated doses up to 250mg once daily for 15 days in healthy human volunteers. Adverse events noted were mild and included headache and gastrointestinal upsets. In patients with schizophrenia AZD8529 has been administered at a dose of 40mg every second day for 28 days. The most common adverse events were headache, schizophrenia, and dyspepsia.
Preclinical studies of up to 3 month duration have been performed. After 1 and 3 month treatment in rats and 3 month treatment in dogs reversible effects on testis were described. Additionally, cataracts were seen after 3 months treatment in the rat and mild effects on liver and ovary are also reported at high dose.
In healthy volunteers, AZD8529 levels in the CSF (taken 6 hours after the day 12 dose of 60mg, QD) was approximately half the plasma free-fraction, suggesting good BBB penetration.
In a 28-day Phase 2 study in schizophrenic patients administered 40mg once daily, there was no change from placebo in the primary outcome measure of the PANSS score.
Suitable for and exclusions
Preclinical reprotoxicology data are available and have not identified any specific risks. Women of child-bearing potential using highly effective contraception can be included.
The preclinical safety findings prompt the careful monitoring for effects on reproductive organs, eyes (slit lamp), and liver in future clinical studies of >3 weeks duration.