Clobenpropit dihydrobromide

Clobenpropit dihydrobromide is a potent histamine H3R antagonist/inverse agonist with a pEC50 of 8.07 for histamine H3LR[1]. Clobenpropit dihydrobromide acts as partial agonist at histamine H4 receptors (Ki 13 nM). Clobenpropit dihydrobromide also binds to serotonin 5-HT3 receptors (Ki 7.4 nM) and α2A/α2C adrenoceptors (Ki 17.4/7.8 nM)[2]. Clobenpropit dihydrobromide increases apoptosis[3].

Research Areas >> Cancer

Signaling Pathways >> Immunology/Inflammation >> Histamine Receptor

Research Areas >> Neurological Disease

Signaling Pathways >> GPCR/G Protein >> Histamine Receptor

Human H3LR:9.44 (pKi)

Rat H3LR:9.75 (pKi)

H4 receptor:13 nM (Ki)

H2 Receptor:5.6 (pKi)

Clobenpropit binds to human H3LR and rat H3LR with pKis of 9.44±0.04 and 9.75±0.01. Clobenpropit exhibits low affinity for histamine H1R or H2R (pKis of 5.2 and 5.6, respectively)[1]. Clobenpropit inhibits [3H]-dopamine transport by SH-SY5Y cells in a concentration dependent manner with maximum inhibition 82.7±2.8 % and IC50 490 nM (pIC50 6.31±0.11)[2]. Clobenpropit is a subunit-selective noncompetitive antagonist at recombinant NMDA receptors (IC50 1 μM for the NR1/NR2B receptor)[2]. Clobenpropit (50 μM) and Gemcitabine (5 μM) combination therapy significantly increases apoptosis of Panc-1, MiaPCa-2 and AsPC-1 compared with control[3]. Apoptosis Analysis[3] Cell Line: Pancreatic cancer cells (Panc-1, MiaPaCa-2 and AsPC-1) Concentration: 50 μM Incubation Time: Result: Enhanced apoptotic cell death in combination of Gemcitabine (5 μM).

The combination treatment of Clobenpropit (every other day intraperitoneal injection at 20 μM per kilogram for 40 d) and Gemcitabine (twice-a-week intraperitoneal injection at 125 mg/kg for 40 d) shows significant tumor growth inhibition[3]. Animal Model: Five-week-old male BALB/c nude mice with Panc-1 xenograft[3] Dosage: 20 μM per kilogram Administration: Intraperitoneal injection; every other day for 40 days. Gemcitabine (twice-a-week intraperitoneal injection at 125 mg/kg for 40 d) Result: The combination treatment showed significant tumor growth inhibition compared with other treatment groups (control 501±92 mg, Gemcitabine 294±46 mg, Clobenpropit 444±167 mg, and combination 154±54 mg).

[1]. Esbenshade TA, et al. Two novel and selective nonimidazole histamine H3 receptor antagonists A-304121 and A-317920: I. In vitro pharmacological effects. J Pharmacol Exp Ther. 2003 Jun;305(3):887-96.

[2]. Mena-Avila E, et al. Clobenpropit, a histamine H3 receptor antagonist/inverse agonist, inhibits [³H]-dopamine uptake by human neuroblastoma SH-SY5Y cells and rat brain synaptosomes. Pharmacol Rep. 2018 Feb;70(1):146-155.

[3]. Paik WH, et al. Clobenpropit enhances anti-tumor effect of gemcitabine in pancreatic cancer. World J Gastroenterol. 2014 Jul 14;20(26):8545-57.