PHCCC is a group I mGluR antagonist with an IC50 value of 3μM [1]. PHCCC acts as the small molecule glutamate receptor enhancer, altering the functions of dendritic cells to metabolize glutamate, skewing cytokine secretion to bias T cell function [2]. PHCCC has been widely used to activate the mGlu6 receptor and regulate the natural calcium current in the sympathetic neurons isolated from the superior cervical ganglia of rats[3].
In vitro, PHCCC treatment (30µM) for 5 minutes significantly reduced the activity of the PI-3-K pathway in D283med cells and DAOY cells, and inhibited cAMP production[4]. In the presence of 1μM retinoic acid (RA), treatment with PHCCC (30µM) for 4 days enhanced the differentiation of mouse embryonic stem cells into neuronal lineage cells, resulting in increased expression of early neural markers Dlx-2 and Nestin[5].
In vivo, PHCCC treatment via a single intracerebroventricular injection (75nmol/2.5μl) for 30 minutes significantly reversed the movement disorders induced by reserpine in rats [6]. Intraperitoneal injection of PHCCC at a dose of 10mg/kg every other day for 20 days significantly inhibited tumor growth in the OS18 xenograft mouse model without affecting the body weight of the mice[7]. Subcutaneous injection of PHCCC at a dose of 3mg/kg every three days for 18 days significantly delayed disease progression and alleviated disease severity in mice with experimental autoimmune encephalomyelitis[8].
References:
[1] Recasens M, Guiramand J, Aimar R, et al. Metabotropic glutamate receptors as drug targets[J]. Current Drug Targets, 2007, 8(5): 651-681.
[2] Fallarino F, Volpi C, Fazio F, et al. Metabotropic glutamate receptor-4 modulates adaptive immunity and restrains neuroinflammation[J]. Nature medicine, 2010, 16(8): 897-902.
[3] Beqollari D, Kammermeier P J. The mGlu4 receptor allosteric modulator N-phenyl-7-(hydroxyimino) cyclopropa [b] chromen-1a-carboxamide acts as a direct agonist at mGlu6 receptors[J]. European journal of pharmacology, 2008, 589(1-3): 49-52.
[4] Iacovelli L, Arcella A, Battaglia G, et al. Pharmacological activation of mGlu4 metabotropic glutamate receptors inhibits the growth of medulloblastomas[J]. Journal of Neuroscience, 2006, 26(32): 8388-8397.
[5] Sarichelou I, Cappuccio I, Ferranti F, et al. Metabotropic glutamate receptors regulate differentiation of embryonic stem cells into GABAergic neurons[J]. Cell Death & Differentiation, 2008, 15(4): 700-707.
[6] Marino M J, Williams Jr D L, O'Brien J A, et al. Allosteric modulation of group III metabotropic glutamate receptor 4: a potential approach to Parkinson's disease treatment[J]. Proceedings of the National Academy of Sciences, 2003, 100(23): 13668-13673.
[7] Kansara M, Thomson K, Pang P, et al. Infiltrating myeloid cells drive osteosarcoma progression via GRM4 regulation of IL23[J]. Cancer discovery, 2019, 9(11): 1511-1519.
[8] Gammon J M, Tostanoski L H, Adapa A R, et al. Controlled delivery of a metabolic modulator promotes regulatory T cells and restrains autoimmunity[J]. Journal of Controlled Release, 2015, 210: 169-178.