N-Desmethyl clomipramine (hydrochloride)

N-Desmethyl clomipramine hydrochloride (Desmethylclomipramine hydrochloride; Norclomipramine hydrochloride) is the orally active major active metabolite of the tricyclic antidepressant Clomipramine (HY-B0457A), possessing multiple activities including anti-inflammatory, antioxidant, antibacterial, and antiparasitic effects. N-Desmethyl clomipramine hydrochloride blocks autophagosome-lysosome fusion, leading to the accumulation of LC3-II, p62, ATG7, WIPI2, and ATG5-12, reactivates the p53/p21 pathway, induces apoptosis through C-PARP and C-CAS3, and inhibits the proliferation, migration, and invasion of renal cancer cells. N-Desmethyl clomipramine hydrochloride inhibits LdTOPIA, inducing R-loop accumulation in the nucleus of Leishmania, ultimately causing parasite death. N-Desmethyl clomipramine hydrochloride can be used for research on depression, metastatic renal cell carcinoma, and leishmaniasis^{[1][2][3][4][5]}. In Vitro:N-Desmethyl clomipramine (Norclomipramine) hydrochloride completely inhibits Mycobacterium tuberculosis topoisomerase-I activity in the DNA relaxation assay^[2].
N-Desmethyl clomipramine hydrochloride effectively blocks autophagic flux in KJ29 and Caki-2 ccRCC cells, leading to the accumulation of the autophagy markers p62 and LC3I/II; it also prevents autophagosome-lysosome fusion, resulting in the accumulation of ATG7, WIPI2, and ATG5-12 in KJ29 and Caki-2 ccRCC cells^[3].
N-Desmethyl clomipramine (1-10 µM; 0-120 h) hydrochloride inhibits the proliferation of KJ29 and Caki-2 ccRCC cells in a dose-dependent manner, reduces migration, and enhances the growth-inhibitory effect of Sunitinib (HY-10255A); it also promotes apoptosis in KJ29 and Caki-2 ccRCC cells and enhances Sunitinib-induced apoptosis through activation of C-PARP and C-CAS3^[3].
N-Desmethyl clomipramine (5 µM) hydrochloride inhibits autophagy and reactivates the p53/p21 pathway in KJ29 and Caki-2 ccRCC cells^[3].
N-Desmethyl clomipramine (Desmethylclomipramine) (0.01-1 μM; 48 h) hydrochloride reduces TNFα secretion and nitrite levels in a dose-dependent manner in mouse primary cortical neuron-BV2 microglia co-cultures, but does not improve neuronal viability^[4].
N-Desmethyl clomipramine (1 μM; 16 h) hydrochloride upregulates Nfe2l2 gene expression in BV2 microglia under both inflammatory and non-inflammatory conditions, but does not regulate the expression of the Nrf2 target genes Gclm, Hmox1, or Nqo1^[4].
N-Desmethyl clomipramine (10-40 μM) hydrochloride inhibits the DNA relaxation activity of LdTOPIA^[5].
N-Desmethyl clomipramine (2-100 μM; 72 h) hydrochloride exhibits potent antileishmanial activity against Leishmania donovani promastigotes and amastigotes, and is effective against clinically isolated antimony-resistant Leishmania isolates BHU575 and BHU814; its cytotoxicity to macrophages (Raw264.7 and THP1) is lower than its antileishmanial activity^[5].
N-Desmethyl clomipramine (10 μM; 0-48 h) hydrochloride treatment induces R-loop formation in Leishmania donovani DD8 parasites, as detected by the DRIB assay^[5].
N-Desmethyl clomipramine (10 μM; 6-48 h) hydrochloride effectively clears Leishmania donovani DD8 amastigotes within RAW264.7 macrophages^[5].
N-Desmethyl clomipramine (10 μM; 48 h) hydrochloride reduces the intracellular amastigote burden of Leishmania donovani DD8, BHU575, and BHU814 in RAW264.7 macrophages^[5]. In Vivo:N-Desmethyl clomipramine (Desmethylclomipramine) (0.05-0.4 mg/kg; intravenous injection; infusion for 10 min; 30 min before PET measurement) hydrochloride occupied NET in non-human primates in a dose- and plasma concentration-dependent manner, with mean K_d values of 0.11 mg/kg and 4.4 ng/mL^[1].