Discovery of a Highly Selective and Potent TRPC3 Inhibitor with High Metabolic Stability and Low Toxicity

Overview

Journal ACS Med Chem Lett

Publisher American Chemical Society

Specialty Chemistry

Date 2021 Apr 16

PMID 33859797

Citations 7

Authors

Sicheng Zhang

Luis O Romero

Shanshan Deng

Jiaxing Wang

Yong Li

Lei Yang

David J Hamilton

Duane D Miller

Francesca-Fang Liao

Julio F Cordero-Morales

Zhongzhi Wu

Wei Li

Affiliations

Soon will be listed here.

Abstract

The overactivation of transient receptor potential canonical 3 (TRPC3) is associated with neurodegenerative diseases and hypertension. Pyrazole 3 (Pyr3) is reported as the most selective TRPC3 inhibitor, but it has two inherent structural limitations: (1) the labile ester moiety leads to its rapid hydrolysis to the inactive Pyr8 , and (2) the alkylating trichloroacrylic amide moiety is known to be toxic. To circumvent these limitations, we designed a series of conformationally restricted Pyr3 analogues and reported that compound maintains high potency and selectivity for human TRPC3 over its closely related TRP channels. It has significantly improved metabolic stability compared with Pyr3 and has a good safety profile. Preliminary evaluation of demonstrated its ability to rescue Aβ-induced neuron damage with similar potency to that of Pyr3 . Collectively, these results suggest that represents a promising scaffold to potentially ameliorate the symptoms associated with TRPC3-mediated neurological and cardiovascular disorders.

Citing Articles

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References

Kiyonaka S, Kato K, Nishida M, Mio K, Numaga T, Sawaguchi Y . Selective and direct inhibition of TRPC3 channels underlies biological activities of a pyrazole compound. Proc Natl Acad Sci U S A. 2009; 106(13):5400-5. PMC: 2664023. DOI: 10.1073/pnas.0808793106. View

Walsh D, Klyubin I, Fadeeva J, Cullen W, Anwyl R, Wolfe M . Naturally secreted oligomers of amyloid beta protein potently inhibit hippocampal long-term potentiation in vivo. Nature. 2002; 416(6880):535-9. DOI: 10.1038/416535a. View

Aydar E, Yeo S, Djamgoz M, Palmer C . Abnormal expression, localization and interaction of canonical transient receptor potential ion channels in human breast cancer cell lines and tissues: a potential target for breast cancer diagnosis and therapy. Cancer Cell Int. 2009; 9:23. PMC: 2737535. DOI: 10.1186/1475-2867-9-23. View

Wang H, Cheng X, Tian J, Xiao Y, Tian T, Xu F . TRPC channels: Structure, function, regulation and recent advances in small molecular probes. Pharmacol Ther. 2020; 209:107497. PMC: 7183440. DOI: 10.1016/j.pharmthera.2020.107497. View

Baixia Hao H, Webb S, Yue J, Moreau M, Leclerc C, Miller A . TRPC3 is required for the survival, pluripotency and neural differentiation of mouse embryonic stem cells (mESCs). Sci China Life Sci. 2018; 61(3):253-265. DOI: 10.1007/s11427-017-9222-9. View

Mori Y, Wakamori M, Miyakawa T, Hermosura M, Hara Y, Nishida M . Transient receptor potential 1 regulates capacitative Ca(2+) entry and Ca(2+) release from endoplasmic reticulum in B lymphocytes. J Exp Med. 2002; 195(6):673-81. PMC: 2193746. DOI: 10.1084/jem.20011758. View

Koenig S, Schernthaner M, Maechler H, Kappe C, Glasnov T, Hoefler G . A TRPC3 blocker, ethyl-1-(4-(2,3,3-trichloroacrylamide)phenyl)-5-(trifluoromethyl)-1H-pyrazole-4-carboxylate (Pyr3), prevents stent-induced arterial remodeling. J Pharmacol Exp Ther. 2012; 344(1):33-40. DOI: 10.1124/jpet.112.196832. View

Riccio A, Medhurst A, Mattei C, Kelsell R, Calver A, Randall A . mRNA distribution analysis of human TRPC family in CNS and peripheral tissues. Brain Res Mol Brain Res. 2003; 109(1-2):95-104. DOI: 10.1016/s0169-328x(02)00527-2. View

Li Y, Calfa G, Inoue T, Amaral M, Pozzo-Miller L . Activity-dependent release of endogenous BDNF from mossy fibers evokes a TRPC3 current and Ca2+ elevations in CA3 pyramidal neurons. J Neurophysiol. 2010; 103(5):2846-56. PMC: 2867575. DOI: 10.1152/jn.01140.2009. View

10.

Huang C . The transient receptor potential superfamily of ion channels. J Am Soc Nephrol. 2004; 15(7):1690-9. DOI: 10.1097/01.asn.0000129115.69395.65. View

11.

Amaral M, Pozzo-Miller L . TRPC3 channels are necessary for brain-derived neurotrophic factor to activate a nonselective cationic current and to induce dendritic spine formation. J Neurosci. 2007; 27(19):5179-89. PMC: 2806846. DOI: 10.1523/JNEUROSCI.5499-06.2007. View

12.

Wang Y, Qi Y, Qi Z, Tsang S . TRPC3 Regulates the Proliferation and Apoptosis Resistance of Triple Negative Breast Cancer Cells through the TRPC3/RASA4/MAPK Pathway. Cancers (Basel). 2019; 11(4). PMC: 6520729. DOI: 10.3390/cancers11040558. View

13.

Philipp S, Strauss B, Hirnet D, Wissenbach U, Mery L, Flockerzi V . TRPC3 mediates T-cell receptor-dependent calcium entry in human T-lymphocytes. J Biol Chem. 2003; 278(29):26629-38. DOI: 10.1074/jbc.M304044200. View

14.

Oda K, Umemura M, Nakakaji R, Tanaka R, Sato I, Nagasako A . Transient receptor potential cation 3 channel regulates melanoma proliferation and migration. J Physiol Sci. 2016; 67(4):497-505. PMC: 10717062. DOI: 10.1007/s12576-016-0480-1. View

15.

Bathina S, Das U . Brain-derived neurotrophic factor and its clinical implications. Arch Med Sci. 2016; 11(6):1164-78. PMC: 4697050. DOI: 10.5114/aoms.2015.56342. View

16.

Schleifer H, Doleschal B, Lichtenegger M, Oppenrieder R, Derler I, Frischauf I . Novel pyrazole compounds for pharmacological discrimination between receptor-operated and store-operated Ca(2+) entry pathways. Br J Pharmacol. 2012; 167(8):1712-22. PMC: 3525873. DOI: 10.1111/j.1476-5381.2012.02126.x. View

17.

Li H, Xu X, Montell C . Activation of a TRPC3-dependent cation current through the neurotrophin BDNF. Neuron. 2000; 24(1):261-73. DOI: 10.1016/s0896-6273(00)80838-7. View

18.

Chen Y, Wang B, Liu D, Li J, Xue Y, Sakata K . Hsp90 chaperone inhibitor 17-AAG attenuates Aβ-induced synaptic toxicity and memory impairment. J Neurosci. 2014; 34(7):2464-70. PMC: 3921421. DOI: 10.1523/JNEUROSCI.0151-13.2014. View

19.

Bush E, Hood D, Papst P, Chapo J, Minobe W, Bristow M . Canonical transient receptor potential channels promote cardiomyocyte hypertrophy through activation of calcineurin signaling. J Biol Chem. 2006; 281(44):33487-96. DOI: 10.1074/jbc.M605536200. View

20.

Cohen R, Torres A, Ma H, Holowka D, Baird B . Ca2+ waves initiate antigen-stimulated Ca2+ responses in mast cells. J Immunol. 2009; 183(10):6478-88. PMC: 3037335. DOI: 10.4049/jimmunol.0901615. View