Calhex 231 hydrochloride is a negative allosteric modulator of the calcium-sensing receptor (CaSR), which can block the accumulation of inositol phosphates induced by Ca2+. Calhex 231 hydrochloride IC50 value in HEK293 cells is 0.39μM[1]. Calhex 231 hydrochloride is commonly used in the research of vascular-related diseases[2]. Calhex 231 hydrochloride can inhibit fibroblast fibrosis[3]. Calhex 231 hydrochloride has also been found to be beneficial in inhibiting the development of cancer[4].
In vitro, pretreatment of primary neonatal rat cardiac fibroblasts with Calhex 231 hydrochloride (3μM) for 48 hours after high glucose (40mM) treatment significantly downregulated the protein expression of CaSR, α-SMA, Col-I, Col-III, MMP2, and MMP9. Calhex 231 hydrochloride also reduced the content of Col-I and Col-III in the cell supernatant and significantly inhibited the migration and proliferation of cardiac fibroblasts[5]. Pretreatment of endothelium-intact rabbit mesenteric arterial segments with Calhex 231 hydrochloride (3μM) for 30 minutes significantly weakened the vasodilatory response induced by extracellular calcium (1mM to 6mM). Calhex 231 hydrochloride also increased the amplitude of vascular contraction peaks[6].
In vivo, Calhex 231 hydrochloride (10μmol/kg/day) was administered via tail vein injection to Wistar rats with heart failure induced by Isoprenaline (170mg/kg/day; 4 days). Calhex 231 hydrochloride significantly improved cardiac systolic and diastolic function, reduced cardiomyocyte apoptosis, and inhibited the endoplasmic reticulum stress and mitochondrial apoptosis pathways[7]. Calhex 231 hydrochloride (10μmol/kg) was administered once daily via intraperitoneal injection to spontaneously hypertensive rats (SHR) from 16 weeks of age until 20 weeks of age. Calhex 231 hydrochloride significantly reduced hypertension-related blood pressure increases, alleviated cardiomyocyte apoptosis, and improved mitochondrial dynamics abnormalities[8].
References:
[1] Petrel C, Kessler A, Maslah F, et al. Modeling and mutagenesis of the binding site of Calhex 231, a novel negative allosteric modulator of the extracellular Ca(2+)-sensing receptor. J Biol Chem. 2003 Dec 5;278(49):49487-94.
[2] Lei Y, Peng X, Hu Y, et al. The Calcilytic Drug Calhex-231 Ameliorates Vascular Hyporesponsiveness in Traumatic Hemorrhagic Shock by Inhibiting Oxidative Stress and miR-208a-Mediated Mitochondrial Fission. Oxid Med Cell Longev. 2020 Dec 3;2020:4132785.
[3] Wolffs K, Li R, Mansfield B, et al. Calcium-Sensing Receptor as a Novel Target for the Treatment of Idiopathic Pulmonary Fibrosis. Biomolecules. 2025 Apr 1;15(4):509.
[4] Yamamura A, Nayeem MJ, Sato M. Calcilytics inhibit the proliferation and migration of human prostate cancer PC-3 cells. J Pharmacol Sci. 2019 Mar;139(3):254-257.
[5] Yuan H, Xu J, Xu X, et al. Calhex231 Alleviates High Glucose-Induced Myocardial Fibrosis via Inhibiting Itch-Ubiquitin Proteasome Pathway in Vitro. Biol Pharm Bull. 2019 Aug 1;42(8):1337-1344.
[6] Greenberg HZE, Jahan KS, Shi J, et al. The calcilytics Calhex-231 and NPS 2143 and the calcimimetic Calindol reduce vascular reactivity via inhibition of voltage-gated Ca2+ channels. Eur J Pharmacol. 2016 Nov 15;791:659-668.
[7] Lu FH, Fu SB, Leng X, et al. Role of the calcium-sensing receptor in cardiomyocyte apoptosis via the sarcoplasmic reticulum and mitochondrial death pathway in cardiac hypertrophy and heart failure. Cell Physiol Biochem. 2013;31(4-5):728-43.
[8] Hong S, Zhang X, Zhang X, et al. Role of the calcium sensing receptor in cardiomyocyte apoptosis via mitochondrial dynamics in compensatory hypertrophied myocardium of spontaneously hypertensive rat. Biochem Biophys Res Commun. 2017 Jun 3;487(3):728-733.
Calhex 231 hydrochloride是一种钙感应受体（CaSR）的负变构调节剂，能够阻断Ca2+诱导的肌醇磷酸酯积累，其在HEK293细胞中的IC50值为0.39μM[1]。Calhex 231 hydrochloride常被用于血管相关疾病的研究[2]。Calhex 231 hydrochloride可抑制成纤维细胞纤维化[3]。Calhex 231 hydrochloride还被发现有利于抑制癌症的发展[4]。
在体外，Calhex 231 hydrochloride（3μM）预处理经高糖（40mM）处理的原代新生大鼠心脏成纤维细胞48h，Calhex 231 hydrochloride显著下调CaSR、α-SMA、Col-I、Col-III、MMP2、MMP9蛋白表达，减少细胞上清液中Col-I、Col-III的含量，能显著抑制心脏成纤维细胞的迁移与增殖[5]。Calhex 231 hydrochloride（3μM）预处理内皮完整的兔肠系膜动脉血管段30min，可显著减弱1mM至6mM外钙诱导的血管的舒张反应，Calhex 231 hydrochloride还能血管收缩峰值幅度[6]。
在体内，Calhex 231 hydrochloride（10μmol/kg/day）通过尾静脉注射，用于处理由Isoprenaline（170mg/kg/day；4day）诱导的心力衰竭模型Wistar大鼠。Calhex 231 hydrochloride显著改善了心脏收缩和舒张功能，减少了心肌细胞凋亡，并抑制了内质网应激和线粒体凋亡通路[7]。Calhex231 hydrochloride（10μmol/kg）每日一次腹腔注射，用于处理16周龄开始直至20周龄的自发性高血压大鼠（SHR）。Calhex231 hydrochloride显著降低了高血压相关的血压升高，减轻了心肌细胞凋亡，并改善了线粒体动力学异常[8]。