AZD9272 and AZD2066: selective and highly central nervous system penetrant mGluR5 antagonists characterized by their discriminative effects

The metabotropic glutamate receptor 5 (mGluR5) antagonists fenobam, MPEP (2-methyl-6-(phenylethynyl)pyridine), and MTEP (3-[(2-methyl-1,3-thiazol-4-yl)ethynyl]pyridine) were previously shown to not cause N-methyl-D-aspartate antagonist-like psychoactive effects in phencyclidine (PCP) drug discrimination studies, but to cause MTEP-like discrimination in rats, suggesting that the psychoactive and psychotomimetic effects reported with fenobam in humans were likely mediated by mGluR5 Antagonist mechanisms. The present study was designed to characterize AZD9272 (3-fluoro-5-(3-(5-fluoropyridin-2-yl)-1,2,4-oxadiazol5-yl)benzonitrile) and AZD2066 [4-(5-{(1R)-1-[5-(3-chlorophenyl)isoxazol-3-yl]ethoxy}-4-methyl-4H-1,2,4-triazol-3-yl)pyridine], two mGluR5 antagonists taken to clinical development for analgesia. AZD9272 was evaluated in several groups of rats trained to discriminate cocaine, PCP, chlordiazepoxide, (-)-Δ(9)-tetrahydrocannabinol [(-)-Δ(9)-THC], or MTEP from no drug. AZD9272 shared discriminative properties with MTEP only. The discriminative half-life was 3.23 hours for MTEP and 21.93 hours for AZD9272 in rats trained to discriminate MTEP from no drug. Other rats were successfully trained to discriminate AZD9272 from no drug. Due to the long duration of action of AZD9272, discrimination training was conducted every other day. AZD9272 caused a dose-dependent increase in AZD9272-appropriate responding. PCP did not cause AZD9272-appropriate responding, whereas MTEP, fenobam, and the mGluR5 Antagonist AZD2066 did. The discriminative half-life of AZD9272 was 24.3 hours in rats trained to discriminate AZD9272 from no drug. It is concluded that the discriminative effects of AZD9272 and AZD2066 are similar to those of previously investigated mGluR5 antagonists and dissimilar to those of cocaine, PCP, chlordiazepoxide, and (-)-Δ(9)-THC. The discriminative half-life of AZD9272 is approximately 7-fold longer than for MTEP. These data support and extend previous findings suggesting that mGluR5 antagonism causes psychoactive effects selectively mediated by mGluR5 mechanisms.