VU 0364770 is a brain-penetrant and positive allosteric modulator of mGlu4 receptors with EC50 values of 290 nM. It also exhibits affinity for MAO-B and MAO-A with Ki values of 0.72 μM and 8.5 μM, respectively.
VU0364770 is a selective and potent positive allosteric modulator (PAM) of mGlu4. VU0346770 exhibits EC50s of 290 nM and 1.1 μM at rat mGlu4 and human mGlu4 receptor, respectively. VU0364770 exhibits antagonist activity at mGlu5 with a potency of 17.9 μM and PAM activity at mGlu6 with a potency of 6.8 μM. VU0364770 also possesses activity at MAO with Ki values of 8.5 and 0.72 μM for human MAO-A and human MAO-B, respectively. VU0364770 produces a concentration-dependent potentiation of the response to an EC20 concentration of glutamate with EC50 of 1.1±0.2 μM and increases the maximal response to glutamate from 100 to 227±17%. 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 mGlu4 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[2].
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