The mGlu4 receptor allosteric modulator N-phenyl-7-(hydroxyimino)cyclopropa[b]chromen-1a-carboxamide acts as a direct agonist at mGlu6 receptors

Effects of the mGlu4 receptor allosteric modulator N-phenyl-7-(hydroxyimino)cyclopropa[b]chromen-1a-carboxamide (PHCCC) were tested on closely related mGlu6 receptors. Modulation of native calcium currents in isolated sympathetic neurons from rat superior cervical ganglion by expressed mGlu4 and mGlu6 receptor was used to assay receptor activity. Glutamate concentration–response curves with and without PHCCC confirmed that the drug is an allosteric modulator of mGlu4 receptor, without direct agonist activity. Conversely, PHCCC directly activates the mGlu6 receptor and does not enhance activity of glutamate. Therefore, PHCCC is a direct mGlu6 receptor agonist, but lacks allosteric modulatory properties.