BAY36-7620: A potent non-competitive mGlu1 receptor antagonist with inverse agonist activity.

L-Glutamate (Glu) activates at least eight different G protein-coupled rece ptors known as metabotropic glutamate (mGlu) receptors, which mostly act as regulators of synaptic transmission. These receptors consist of two domain s: an extracellular domain in which agonists bind and a transmembrane hepta helix region involved in G protein activation. Although new mGlu receptor a gonists and antagonists have been described, few are selective for a single mGlu subtype. Here, we have examined the effects of a novel compound, BAY3 6-7620 [(3aS, 6aS)-6a-Naphtalen-2-ylmethyl-5-methyliden-hexahydro-cyclopent al[c]furan-1-on], on mGlu receptors (mGlu1-8), transiently expressed in hum an embryonic kidney 293 cells. BAY36-7620 is a potent (IC50 = 0.16 muM) and selective antagonist at mGlu1 receptors and inhibits > 60% of mGlu1a recep tor constitutive activity (IC50 = 0.38 muM). BAY36-7620 is therefore the fi rst described mGlu1 receptor inverse agonist. To address the mechanism of a ction of BAY36-7620, Glu dose-response curves were performed in the presenc e of increasing concentrations of BAY36-7620. The results show that BAY36-7 620 largely decreases the maximal effect of Glu. Moreover, BAY36-7620 did n ot displace the [H-3] quisqualate binding from the Glu-binding pocket, furt her indicating that BAY36-7620 is a noncompetitive mGlu1 antagonist. Studie s of chimeric receptors containing regions of mGlu1 and regions of DmGluA, mGlu2, or mGlu5, revealed that the transmembrane region of mGlu1 is necessa ry for activity of BAY36-7620. Transmembrane helices 4 to 7 are shown to pl ay a critical role in the selectivity of BAY36-7620. This specific site of action of BAY36-7620 differs from that of competitive antagonists and indic ates that the transmembrane region plays a pivotal role in the agonist-inde pendent activity of this receptor. BAY36-7620 will be useful to further del ineate the functional importance of the mGlu1 receptor, including its putat ive agonist-independent activity.