61350-00-3

VU0364770 is a selective positive allosteric modulator of mGlu ₄ in recombinant systems. VU0364770 is a potent PAM of multiple signaling pathways that enhances the response of the rat and human mGlu ₄ receptors to the endogenous agonist glutamate. VU0364770 produces a concentration-dependent potentiation of the response to an EC ₂₀ concentration of glutamate with EC ₅₀ of 1.1±0.2 μM and increases the maximal response to glutamate from 100 to 227±17%. Because of concerns that this chemical scaffold might possess activity at MAO, full IC ₅₀ determinations is performed for VU0364770 at the MAO-A and MAO-B isoforms; these studies result in K _i s of 8.5 and 0.72 μM for human MAO-A and human MAO-B, respectively. When tested at a 10 μM concentration at each mGlu receptor, VU0364770 exhibits weak PAM activity (4.3-fold left shift of the glutamate CRC) at mGlu6 and antagonist activity (3.3-fold right shift of the glutamate CRC) at mGlu5 (compare to the 16.5-fold left shift of the glutamate concentration-response for mGlu ₄ at 10 μM). When further evaluated in a full concentration-response curve format, VU0364770 exhibits antagonist activity at mGlu ₅ with a potency of 17.9±5.5 μM and PAM activity at mGlu ₆ with a potency of 6.8±1.7 μM (compare with the potency of VU0364770 on the rat mGlu ₄ receptor of 290±80 nM).

VU0364770 exhibits suitable pharmacokinetic properties for systemic dosing in animal models. After intravenous administration, VU0364770 is rapidly clears from the systemic circulation (165 ml/min/kg) and exhibits a volume of distribution of 2.92 L/kg. VU0364770 is a highly protein-bound ligand displaying free fractions of 2.7 and 1.8% in human and rat plasma, respectively. VU0364770 also shows an improved pharmacokinetic profile relative to previously reported mGlu ₄ PAMs with enhanced central penetration and a total brain-to-plasma ratio of more than 1 after systemic administration of a 10 mg/kg dose. VU0364770 produces a dose-dependent reversal of haloperidol-induced catalepsy. VU0364770 dose-dependently reverses haloperidol (0.75 mg/kg)-induced catalepsy in rats, significant at doses of 10 to 56.6 mg/kg, after subcutaneous dosing (F _6,69 =8.04; p<0.001).