AZD 9272

AZD 9272 is a selective, orally active and brain penetrant mGluR5 antagonist with IC₅₀s of 2.6 nM and 7.6 nM for rat and human receptors, respectively. AZD 9272 shows >3900-fold selectivity over other mGlu receptors^[1]2]. IC50 & Target:mGluR5^{[1] In Vitro:AZD 9272 causes a concentration dependent decrease in the magnitude of the intracellular Ca2+ response to 1.5 μM of the mGluR group I selective agonist DHPG in both the human and the rat mGluR5 expressing cell lines. The maximal inhibition is 100%. Increasing concentrations of AZD9272 causes a decrease in the potency and the maximal response of DHPG. AZD9272 completely reverses the glutamate-stimulated (EC₈₀, 80 μM) phosphatidyl inositol hydrolysis in human mGluR5-GHEK cells in a concentration-dependent manner, with IC₅₀ of 26 nM[2].
In Vivo:The clearance of AZD 9272 is low following a single intravenous dose at 3 μmol/kg and AZD 9272 is eliminated from plasma with terminal half-lives between 2 and 6 h. The terminal half-lives following oral dosing are similar to the half-lives following intravenous dosing, yielded a brain-to-plasma ratio close to 1. The volume of distribution at steady state is intermediate for AZD9272[1].
AZD9272 at 2.84 mg/kg causes greater than 80% and typically more than 99% MTEP-appropriate responding up to 20 hours after dose, with a decline to approximately 20% at 24 hours after dose, yielding a t_1/2 of 21.93 hours, and causes no systematic effects on response rates. The first time point at which AZD9272 causes >90% MTEP-appropriate responding is at 30 minutes after dose[2].}