Lu AF21934

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Background

EC50: 500 nMLu AF21934 is a positive allosteric modulator of mGlu4 receptors.The mGlu4 receptor subtype of the group III mGlu is mainly a presynaptic auto- or hetero-receptor. Its stimulation results in an inhibition of glutamatergic or GABAergic transmission and release In vitro: Lu AF21934 has been identified as a brain-penetrating positive allosteric modulator of mGlu4 receptors. In broad in-vitro screens, Lu AF21934 could potentiate the glutamate response at the mGlu4 receptor with an Emax=120% and a glutamate fold-shift FS=5. Lu AF21934 did not showed any significant affinity for 70 GPCRs at 10 μM, but acted as a weak positive allosteric modulator of mGlu6 receptor, as well as an antagonist of adenosine A2A and 5-HT2B receptors [1]. In vivo: In rats, harmaline triggered tremor as manifested by an increase in the power within 9-15Hz band and in the tremor index. Harmaline also induced a biphasic effect on mobility, initially inhibiting the exploratory locomotor activity of rats, followed by an increase in their basic activity. Lu AF21934 at 0.5-5 mg/kg sc did not influence tremor but at doses of 0.5 and 2.5 mg/kg reversed harmaline-induced hyperactivity. MGlu4 mRNA expression was found to be high in the cerebellar cortex and low in the inferior olive [1]. Clinical trial: Up to now, Lu AF21934 is still in the preclinical development stage.

Reference:[1] Ossowska K,Wardas J,Berghauzen-Maciejewska K,et al. Lu AF21934, a positive allosteric modulator of mGlu4 receptors, reduces the harmaline-induced hyperactivity but not tremor in rats. Neuropharmacology.2014 Aug;83:28-35.