Target validation: Weak selectivity of LY341495 for mGluR2 over mGluR4 makes glutamate a less selective agonist

Metabotropic glutamate receptors (mGluRs) are class C G protein coupled receptors with widespread expression in the central nervous system. There are eight mGluRs in the mammalian genome. Research on mGluRs 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 mGluR family. LY341495 has been used for decades as a potent and selective group II mGluR antagonist. The selectivity of LY341495 was investigated here between mGluR2, a group II mGluR, and mGluR4, a group III receptor, heterologously expressed in adult rat sympathetic neurons from the superior cervical ganglion (SCG), which provides a null‐mGluR background upon which mGluRs were examined in isolation. The compound does in fact selectively inhibit mGluR2 over mGluR4, but in such a way that it makes signaling of the two receptors more difficult to distinguish. The glutamate potency of mGluR2 is about 10‐fold higher than mGluR4. 50 nmol L？1 LY341495 did not alter mGluR4 signaling but shifted the mGluR2 glutamate dose‐response about 10‐fold, such that it overlapped more closely with that of mGluR4. Increasing the LY341494 dose to 500 nmol L？1 further shifted the glutamate dose‐response of mGluR2 by another ~10‐fold, but also shifted that of mGluR4 similarly. Thus, while glutamate is a moderately selective agonist of mGluR2 over mGluR4 when applied alone, in the presence of increasing concentrations of LY341495, this selectivity of glutamate is lost