JHU37160 (DREADD ligand)

Overview

JHU37160 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 1.9 nM (hM3Dq) and 3.6 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.

JHU37160 activates hM3Dq and hM4Di with high potency and efficacy in fluorescent and BRET-based assays in HEK-293 cells (EC₅₀ values are 18.5 and 0.2 nM at hM3Dq and hM4Di respectively.

Occupancy

JHU37160 exhibits high in vivo DREADD occupancy and was not reported to be a P-gp substrate.

In vivo application

JHU37160 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).

In in vivo electrophysiology experiments in mice, JHU37160 produces rapid and potent hM4Di-driven inhibition of light-evoked neuronal activation (at a dose of 0.1 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.

Hydrochloride form recently shown to have dose-dependent anxiogenic effects in male Wistar and Long-Evans rats, regardless of DREADD expression, with no impact on locomotor behvaiour suggesting that high doses (e.g. 1mg/kg) should be avoided in chemogenetic experiments designed to evaluate circuit manipulation on anxiety-like behavior in rats.

Water soluble version also available.

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