AZD9272 and AZD2066: Selective and Highly Central Nervous System Penetrant mGluR5 Antagonists Characterized by Their Discriminative Effects

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 -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 (2)-D 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.

Discovery of N-(5-Fluoropyridin-2-yl)-6-methyl-4-(pyrimidin-5-yloxy)picolinamide (VU0424238): A Novel Negative Allosteric Modulator of Metabotropic Glutamate Receptor Subtype 5 Selected for Clinical Evaluation

“…Both compounds are structurally similar disubstituted alkynes, a motif that has been exploited for the design of several other highly optimized mGlu 5 NAM compounds. 4,5 While results from clinical studies have been reported with nonalkyne based mGlu 5 NAMs such as 3 (fenobam), 17,18 4 (AZD9272), 19,20 and 5 (AZD2066), 19,20 the most highly studied and advanced clinical compounds are three alkyne mGlu 5 NAMs: 6 (mavoglurant), 14,21−25 7 (basimglurant), 26−29 and 8 (dipraglurant) 30,31 (Figure 1). Still, failures to reach primary clinical end points with 6 (14,22,23) and 7 (28) point to the continued need for highly optimized mGlu 5 NAMs.…”

VU0477573: Partial Negative Allosteric Modulator of the Subtype 5 Metabotropic Glutamate Receptor with In Vivo Efficacy

“…Therefore, complete inhibition of mGlu 5 may mimic the effects of NMDAR blockade in vivo. Early clinical trials using fenobam reported effects that dissociative side effects (Pecknold et al, 1982) and serious psychotomimetic side effects were recently reported for a newer class of mGlu 5 NAM (Swedberg and Raboisson, 2014). Unfortunately, these adverse effects were not predicted in preclinical studies; however, partial NAMs may be useful in treatment regimens where one desires to maintain some measure of receptor activity while inhibiting the ability of the native orthosteric agonist to induce excessive receptor activation.…”

Drug Discrimination

“…It can also keep track of individual animals' progress against preset criteria for when a particular animal is available for testing and what test to conduct (e.g., [31,32]). Data can be stored as text files, in calculation sheets, or in a secure database.…”

“…For example, in rats trained to discriminate the novel mGluR5 antagonists MTEP and AZD9272, novel psychoactive effects were discovered and characterized [31,32] and AZD9272 was shown to cause hallucinations in human studies (see Ref. Although novel compounds may have psychoactive properties that prove dissimilar to those of known drugs of abuse based on testing in appropriate drug discrimination assays, the absence of discriminative (psychoactive) properties similar to those of known drugs of abuse is not a guarantee against the fact that the novel compound may possess heretofore unknown properties that may mediate psychoactive effects in humans and pose a potential risk of abuse.…”