Deschloroclozapine is a high-affinity, selective, and metabolically stable muscarinic DREADD agonist. Deschloroclozapine can rapidly cross the blood-brain barrier and effectively activate both excitatory hM3Dq and inhibitory hM4Di DREADD receptors[1-2]. Deschloroclozapine is primarily used in neuroscience for chemogenetic research to precisely modulate neuronal activity[3-4].
In vivo, In transgenic neuropathic pain model rats expressing hM3Dq, subcutaneous injection of Deschloroclozapine (0.1mg/kg) for 120 minutes significantly increased serum OXT levels and rapidly raised the rats' mechanical pain threshold[5]. In transgenic mice expressing hM3Dq, intraperitoneal administration of Deschloroclozapine (1mg/kg) for 5–10 minutes rapidly enhanced neuronal activity via hM3Dq, with an efficacy more than 2.5 times greater than that of Clozapine N-oxide (CNO; 100μg/kg), and brain concentrations of Deschloroclozapine reached approximately 100 nM at 30 minutes[6].
References:
[1] Maggs JL, Williams D, Pirmohamed M, et al. The metabolic formation of reactive intermediates from clozapine, a drug associated with agranulocytosis in man. J Pharmacol Exp Ther. 1995 Dec;275(3):1463-75.
[2] Zhang S, Gumpper RH, Huang XP, et al. Molecular basis for selective activation of DREADD-based chemogenetics. Nature. 2022 Dec;612(7939):354-362.
[3] Nentwig TB, Obray JD, Vaughan DT, et al. Behavioral and slice electrophysiological assessment of DREADD ligand, deschloroclozapine (DCZ) in rats. Sci Rep. 2022 Apr 21;12(1):6595.
[4] Hu F, Morris PJ, Bonaventura J, et al. 18F-labeled radiotracers for in vivo imaging of DREADD with positron emission tomography. Eur J Med Chem. 2021 Mar 5;213:113047.
[5] Nagai Y, Miyakawa N, Takuwa H, et al. Deschloroclozapine, a potent and selective chemogenetic actuator enables rapid neuronal and behavioral modulations in mice and monkeys. Nat Neurosci. 2020 Sep;23(9):1157-1167.
[6] Shimizu M, Yoshimura M, Baba K, et al. Deschloroclozapine exhibits an exquisite agonistic effect at lower concentration compared to clozapine-N-oxide in hM3Dq expressing chemogenetically modified rats. Front Neurosci. 2023 Nov 30;17:1301515.
Deschloroclozapine是一种高亲和力、选择性且代谢稳定的毒蕈碱DREADD激动剂，Deschloroclozapine能快速穿透血脑屏障，有效激活兴奋性hM3Dq和抑制性hM4Di DREADD受体[1-2]。Deschloroclozapine主要用于神经科学领域的化学遗传学研究，以精确调控神经元活动[3-4]。
在体内，对表达hM3Dq的转基因的神经病理性疼痛模型大鼠，皮下注射Deschloroclozapine（0.1mg/kg）处理120分钟，Deschloroclozapine显著升高血清OXT浓度，且快速提大鼠的机械痛阈[5]。对表达hM3Dq的转基因小鼠腹腔注射Deschloroclozapine（1mg/kg）处理5-10分钟，Deschloroclozapine通过hM3Dq快速增强神经元活性，效果强度为Clozapine N-oxide（CNO；100μg/kg）的2.5倍以上，且脑内Deschloroclozapine浓度在30分钟时达100nM[6]。