VU0364770

61350-00-3

C12H9ClN2O

DMSO : >= 100 mg/mL (429.79 mM)

GPCR/G Protein; Neuronal Signaling

VU0364770 is an allosteric of metabotropic glutamate receptor 4 (mGlu₄) modulator, which exhibits a EC₅₀ of 1.1+/-0.2 uM at human mGlu₄. IC50 & Target: EC50: 1.1+/-0.2 uM (mGlu₄)^[1] In Vitro: VU0364770 is a selective positive allosteric modulator of mGlu₄ in recombinant systems. VU0364770 is a potent PAM of multiple signaling pathways that enhances the response of the rat and human mGlu₄ receptors to the endogenous agonist glutamate. VU0364770 produces a concentration-dependent potentiation of the response to an EC₂₀ concentration of glutamate with EC₅₀ of 1.1+/-0.2 uM 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 IC₅₀ determinations is performed for VU0364770 at the MAO-A and MAO-B isoforms; these studies result in K_is of 8.5 and 0.72 uM for human MAO-A and human MAO-B, respectively. When tested at a 10 uM 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 mGlu₄ at 10 uM). When further evaluated in a full concentration-response curve format, VU0364770 exhibits antagonist activity at mGlu₅ with a potency of 17.9+/-5.5 uM and PAM activity at mGlu₆ with a potency of 6.8+/-1.7 uM (compare with the potency of VU0364770 on the rat mGlu₄ receptor of 290+/-80 nM)^[1]. In Vivo: 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 (F_{6, 69}=8.04; p<0.001)^[1].