Advancements in Group II mGluR Agonism: The Development and Evaluation of Fluorinated Bicyclohexane Derivatives

A study was conducted on a compound known as LY354740, which is a selective and orally effective agonist for group II metabotropic glutamate receptors (mGluRs). Researchers were intrigued by a conformationally constrained version of this compound due to its increased selectivity and oral activity. To enhance these properties, they introduced a fluorine atom to the compound, resulting in a new compound, MGS0008, which maintained its agonist activity for mGluR2 and mGluR3 and showed improved oral efficacy in treating phencyclidine (PCP)-induced hyperactivity and head-weaving behavior in rats.

Further research led to the development of another compound, (-)-11, with high agonist activity for group II mGluRs, comparable to the previous compounds. The focus then shifted to modifying the CH2 group at the C4 position of compound 11, leading to the creation of compound 5 and 6 with increased agonist activity. A carbonyl group was chosen for the C4 position in compound 11, resulting in compound MGS0028, which demonstrated exceptionally potent agonist activity for mGluR2 and mGluR3, but not for other mGluRs. MGS0028 also showed strong inhibitory effects on PCP-induced behaviors in rats.

In conclusion, both MGS0008 and MGS0028 emerged as potent, selective, and orally active group II mGluR agonists. These compounds have potential applications in understanding the roles of mGluRs and could be instrumental in the treatment of schizophrenia.