Deschloroclozapine

Deschloroclozapine is a potent, high affinity, selective, metabolically stable agonist of muscarinic-based DREADDs. Deschloroclozapine inhibites [3H]quinuclidinyl benzilate (QNB) binding to hM3Dq and hM4Di with Ki of 6.3 and 4.2 nM. Deschloroclozapine is reported with utility in both mice and non-human primates for a variety of applications[1].

Deschloroclozapine has greater potencies for DREADDs than previous agonists in vitro. Deschloroclozapine is a potent agonist for hM3Dq with an EC50=0.13 nM. Deschloroclozapine is also a potent agonist for hM4Di with an EC50=0.081 nM[1].Deschloroclozapine is a potent and selective agonist for hM3Dq and hM4Di, it does not display significant agonistic activity for any of the 318 tests wild-type GPCRs at <10 nM[1].

Deschloroclozapine (100 μg/kg; i.v.) exhibits good brain concentration profiles and biostability. Pharmacokinetic studies confirmed that Deschloroclozapine is rapidly accumulated in mouse brains and monkey CSF, while its metabolites are negligible[1].Deschloroclozapine (1 μg/kg; i.p.) selectively and rapidly enhances neuronal activity via hM3Dq-DREADD in vivo, Deschloroclozapine can also be utilized for in vivo neuronal silencing by activating hM4Di, an inhibitory DREADD[1].Deschloroclozapine (1-100 μg/kg; i.v.) selectively induces hM3Dq-mediated metabolic activity[1].Deschloroclozapine (100 μg/kg; i.m.) selectively induces behavioral deficits in hM4Di-expressing monkeys[1]. Animal Model: Macaque monkey; 2.8-8.0 kg; age 3-10 years[1]

[1]. Yuji Nagai, et al. Deschloroclozapine: a potent and selective chemogenetic actuator enables rapid neuronal and behavioral modulations in mice and monkeys. bioRxiv.