Target validation: Weak selectivity of LY 341495 for mG luR2 over mG luR4 makes glutamate a less selective agonist

Metabotropic glutamate receptors ( mG luRs) are class C G protein coupled receptors with widespread expression in the central nervous system. There are eight mG luRs in the mammalian genome. Research on mG luRs relies on the availability of selective compounds. While many selective allosteric compounds have been described, selectivity of orthosteric agonists and antagonists has been more difficult due to the similarity of the glutamate binding pocket across the mG luR family. LY 341495 has been used for decades as a potent and selective group II mG luR antagonist. The selectivity of LY 341495 was investigated here between mG luR2, a group II mG luR, and mG luR4, a group III receptor, heterologously expressed in adult rat sympathetic neurons from the superior cervical ganglion ( SCG ), which provides a null‐ mG luR background upon which mG luRs were examined in isolation. The compound does in fact selectively inhibit mG luR2 over mG luR4, but in such a way that it makes signaling of the two receptors more difficult to distinguish. The glutamate potency of mG luR2 is about 10‐fold higher than mG luR4. 50 nmol L −1 LY 341495 did not alter mG luR4 signaling but shifted the mG luR2 glutamate dose‐response about 10‐fold, such that it overlapped more closely with that of mG luR4. Increasing the LY 341494 dose to 500 nmol L −1 further shifted the glutamate dose‐response of mG luR2 by another ~10‐fold, but also shifted that of mG luR4 similarly. Thus, while glutamate is a moderately selective agonist of mG luR2 over mG luR4 when applied alone, in the presence of increasing concentrations of LY 341495, this selectivity of glutamate is lost.