Skip to Content
Merck
  • AZD9272 and AZD2066: selective and highly central nervous system penetrant mGluR5 antagonists characterized by their discriminative effects.

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

The Journal of pharmacology and experimental therapeutics (2014-05-31)
Michael D B Swedberg, Patrick Raboisson
ABSTRACT

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.

MATERIALS
Product Number
Brand
Product Description

Supelco
Ethanol solution, certified reference material, 2000 μg/mL in methanol
Supelco
Dehydrated Alcohol, Pharmaceutical Secondary Standard; Certified Reference Material
Supelco
(±)-Δ9-THC solution, 100 μg/mL in heptane, ampule of 1 mL, Cerilliant®
USP
Dehydrated Alcohol, United States Pharmacopeia (USP) Reference Standard
Sigma-Aldrich
Ethanol, purum, secunda spirit, denaturated with 2% 2-butanone, S15, ~96% (based on denaturant-free substance)
Sigma-Aldrich
Ethanol, tested according to Ph. Eur.
Sigma-Aldrich
Ethyl alcohol, Pure, 190 proof, ACS spectrophotometric grade, 95.0%
Supelco
Ethanol, standard for GC
Sigma-Aldrich
Ethanol, for residue analysis
Sigma-Aldrich
Ethyl alcohol, Pure, 200 proof, anhydrous, ≥99.5%
Sigma-Aldrich
Cocaine free base
Sigma-Aldrich
Ethyl alcohol, Pure, 190 proof, for molecular biology
Sigma-Aldrich
AZD2066, ≥98% (HPLC)
Sigma-Aldrich
Ethanol, purum, absolute ethanol, denaturated with 2% 2-butanone, A15 MEK1, ≥99.8% (based on denaturant-free substance)
Sigma-Aldrich
Ethanol, purum, fine spirit, denaturated with 2% 2-butanone, F25 MEK1, ~96% (based on denaturant-free substance)
Sigma-Aldrich
Ethanol, purum, fine spirit, denaturated with 4.8% methanol, F25 METHYL1, ~96% (based on denaturant-free substance)
Sigma-Aldrich
Ethanol, purum, absolute ethanol, denaturated with 4.8% isopropanol, A15 IPA1, ≥99.8% (based on denaturant-free substance)
Sigma-Aldrich
Ethanol, BioUltra, for molecular biology, ≥99.8%, (absolute alcohol, without additive, A15 o1)
Sigma-Aldrich
Ethyl alcohol, Pure, 200 proof, meets USP testing specifications
Sigma-Aldrich
Ethyl alcohol, Pure, 200 proof, ACS reagent, ≥99.5%