JHU37152 (DREADD ligand)

Overview

JHU37152 is reported to be a novel DREADD agonist with high in vivo DREADD potency for CNS applications.

It has high affinity in vitro for hM3Dq and hM4Di (K_i values are 1.8 nM (hM3Dq) and 8.7 nM (hM4Di).

It selectively displaces [³H]clozapine from DREADDs and not from other clozapine-binding sites at concentrations up to 10 nM when tested for in situ [3H]clozapine displacement in brain tissue from WT and D₁-DREADD mice.

JHU37152 activates hM3Dq and hM4Di with high potency and efficacy in fluorescent and BRET-based assays in HEK-293 cells (EC₅₀ values are 5 and 0.5 nM at hM3Dq and hM4Di respectively.

Occupancy

JHU37152 exhibits high in vivo DREADD occupancy and was not reported to be a P-gp substrate.

In vivo application

JHU37152 is reported to be a potent in vivo DREADD agonist, which selectively inhibits locomotor activity in D₁-hM3Dq and D₁-hM4Di mice without any significant locomotor effects observed in wild type (WT) mice (at doses ranging 0.01 - 1 mg/kg).

It also produces robust and selective increases in hM3Dq-stimulated locomotion in rats expressing hM3Dq in tyrosine hydroxylase expressing neurons (at doses ranging 0.01 – 0.3 mg/kg).

While its selectivity is not ideal (i.e. comparable to clozapine), its high in vivo potency allows for dose adjustments with minimal off-target effects. The compound exhibits promising characteristics for DREADD use in monkeys.

Water soluble version also available.

Sold under license from the NIH, US patent pending 62/627,527