Deschloroclozapine dihydrochlorideは高親和性で、選択的で、代謝的に安定しているムスカリンDREADD作動剤である。Deschloroclozapine dihydrochlorideは、血液脳関門を速やかに通過し、興奮性hM3Dqと抑制性hM4Di DREADD受容体の両方を効果的に活性化できる[1-2]。Deschloroclozapine dihydrochlorideは主に、神経化学分野の化学遺伝学の研究に使われ、神経活動を精確に調節する[3-4]。
In vivo（体内）実験で、hM3Dqを発現する遺伝子組み換え神経障害性疼痛モデルラットで、Deschloroclozapine dihydrochloride（0.1mg/kg）を120分間皮下注射したところ、血清OXTのレベルが著しく増え、ラットの機械的疼痛閾値が速やかに上昇した[5]。hM3Dqを発現する遺伝子組み換えマウスで、Deschloroclozapine dihydrochloride（1mg/kg）を5-10分間腹腔内投与したところ、hM3Dqを通じて、神経活動が速やかに増強し、効果はClozapine N-oxide（CNO；100μg/kg）よりも2.5倍以上で、Deschloroclozapine dihydrochlorideの脳内濃度は30分で約100nMに達した[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 dihydrochloride (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 dihydrochloride, 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 dihydrochloride 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.