Deschloroclozapine

Cas：1977-07-7

Product Information：

Deschloroclozapine is a high affinity and highly potent activator of muscarinic DREADDs. It is a derivative of clozapine, and exhibits 100-fold greater affinity for hM3Dq and hM4Di compared to clozapine N-oxide, and 50-fold greater affinity compared to DREADD agonist 21. Deschloroclozapine displays low 'off-target' receptor binding and rapid binding and activation of hM3Dq and hM4Di in mice and non-human primates. It also induces spatial memory deficits in non-human primates expressing hM4Di in the prefrontal cortex.

Chemical Formula: C18H20N4

Exact Mass: 292.1688

Molecular Weight: 292.386

Elemental Analysis: C, 73.94; H, 6.89; N, 19.16

Synonym:

1977-07-7

Deschloroclozapine

11-(4-Methyl-1-piperazinyl)-5H-dibenzo(b,e)(1,4)diazepine

Dopamine serotonin antagonist-1

11-(4-Methylpiperazin-1-yl)-5H-dibenzo[b,e][1,4]diazepine

BRN 0761696

CHEMBL73538

6-(4-methylpiperazin-1-yl)-11H-benzo[b][1,4]benzodiazepine

11-(4-Methyl-piperazin-1-yl)-5H-dibenzo[b,e][1,4]diazepine

5H-DIBENZO(b,e)(1,4)DIAZEPINE, 11-(4-METHYL-1-PIPERAZINYL)-

11-(4-Methyl-1-piperazinyl)-5H-dibenzo[b,e][1,4]diazepine

SCHEMBL141020

CTK4E2257

DTXSID80173463

CS-M3647

KS-00000M5A

BDBM50010591

ZINC26377671

AK482971

AS-70338

HY-42110

LS-60902

5-25-11-00363 (Beilstein Handbook Reference)

5H-Dibenzo[b,e][1,4]diazepine,11-(4-methyl-1-piperazinyl)-

10-(4-methylpiperazin-1-yl)-2,9-diazatricyclo[9.4.0.0(3),?]pentadeca-1(11),3,5,7,9,12,14-heptaene

Chemical Name:

11-(4-methylpiperazin-1-yl)-5H-dibenzo[b,e][1,4]diazepine

InChi Key:

VQHITFFJBFOMBG-UHFFFAOYSA-N

InChi Code: InChI=1S/C18H20N4/c1-21-10-12-22(13-11-21)18-14-6-2-3-7-15(14)19-16-8-4-5-9-17(16)20-18/h2-9,19H,10-13H2,1H3

Smiles Code:

CN1CCN(CC1)C2=NC3=C(NC4=CC=CC=C24)C=CC=C3

Technical Data：

Appearance: Solid powder

Purity: >98% (or refer to the Certificate of Analysis)

Shipping Condition: Shipped under ambient temperature as non-hazardous chemical. This product is stable enough for a few weeks during ordinary shipping and time spent in Customs.

Storage Condition: Room Temperature

Solubility: Soluble in DMSO

Shelf Life: >3 years if stored properly

Drug Formulation: This drug may be formulated in DMSO

Stock Solution Storage: 0 - 4 C for short term (days to weeks), or -20 C for long term (months).

HS Tariff Code: 2934.99.9001

In Vitro:

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.

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.

In Vivo:

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.

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.

Deschloroclozapine (100 μg/kg; i.m.) selectively induces behavioral deficits in hM4Di-expressing monkeys.

References：

1. Nagai Y, Miyakawa N, Takuwa H, Hori Y, Oyama K, Ji B, Takahashi M, Huang XP, Slocum ST, DiBerto JF, Xiong Y, Urushihata T, Hirabayashi T, Fujimoto A, Mimura K, English JG, Liu J, Inoue KI, Kumata K, Seki C, Ono M, Shimojo M, Zhang MR, Tomita Y, Nakahara J, Suhara T, Takada M, Higuchi M, Jin J, Roth BL, Minamimoto T. 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. doi: 10.1038/s41593-020-0661-3. Epub 2020 Jul 6. PMID: 32632286.

2. Upright NA, Baxter MG. Effect of chemogenetic actuator drugs on prefrontal cortex-dependent working memory in nonhuman primates. Neuropsychopharmacology. 2020 Oct;45(11):1793-1798. doi: 10.1038/s41386-020-0660-9. Epub 2020 Mar 19. PMID: 32193513.

3. Zhang GO, McKay G, Hubbard JW, Midha KK. Application of electrospray mass spectrometry in the identification of intact glucuronide and suplate conjugates of clozapine in rat. Xenobiotica. 1996 May;26(5):541-50. doi: 10.3109/00498259609046730. PMID: 8736064.

4. Maggs JL, Williams D, Pirmohamed M, Park BK. 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. PMID: 8531117.

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