Open AccessA modulator of the low-voltage-activated T-type calcium channel that reverses HIV glycoprotein 120-, paclitaxel-, and spinal nerve ligation-induced peripheral neuropathies
Author(s) -
Sanjun Cai,
Peter Tuohy,
Chunlong Ma,
Naoya Kitamura,
Kimberly Gómez,
Yuan Zhou,
Dongzhi Ran,
Shreya S. Bellampalli,
Jie Yu,
Shizhen Luo,
Angie Dorame,
Nancy Yen Ngan Pham,
G Molnár,
John M. Streicher,
Marcel Pátek,
Samantha PerezMiller,
Aubin Moutal,
Jun Wang,
Rajesh Khanna
Publication year - 2020
Publication title -
pain
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 2.524
H-Index - 258
eISSN - 1872-6623
pISSN - 0304-3959
DOI - 10.1097/j.pain.0000000000001955
Subject(s) - t type calcium channel , voltage dependent calcium channel , dorsal root ganglion , chemistry , calcium channel , depolarization , excitatory postsynaptic potential , sodium channel , n type calcium channel , biophysics , pharmacology , calcium , neuroscience , spinal cord , receptor , biology , biochemistry , organic chemistry , sodium
The voltage-gated calcium channels CaV3.1-3.3 constitute the T-type subfamily, whose dysfunctions are associated with epilepsy, psychiatric disorders, and chronic pain. The unique properties of low-voltage-activation, faster inactivation, and slower deactivation of these channels support their role in modulation of cellular excitability and low-threshold firing. Thus, selective T-type calcium channel antagonists are highly sought after. Here, we explored Ugi-azide multicomponent reaction products to identify compounds targeting T-type calcium channel. Of the 46 compounds tested, an analog of benzimidazolonepiperidine-5bk (1-{1-[(R)-{1-[(1S)-1-phenylethyl]-1H-1,2,3,4-tetrazol-5-yl}(thiophen-3-yl)methyl]piperidin-4-yl}-2,3-dihydro-1H-1,3-benzodiazol-2-one) modulated depolarization-induced calcium influx in rat sensory neurons. Modulation of T-type calcium channels by 5bk was further confirmed in whole-cell patch clamp assays in dorsal root ganglion (DRG) neurons, where pharmacological isolation of T-type currents led to a time- and concentration-dependent regulation with a low micromolar IC50. Lack of an acute effect of 5bk argues against a direct action on T-type channels. Genetic knockdown revealed CaV3.2 to be the isoform preferentially modulated by 5bk. High voltage-gated calcium, as well as tetrodotoxin-sensitive and -resistant sodium, channels were unaffected by 5bk. 5bk inhibited spontaneous excitatory postsynaptic currents and depolarization-evoked release of calcitonin gene-related peptide from lumbar spinal cord slices. Notably, 5bk did not bind human mu, delta, or kappa opioid receptors. 5bk reversed mechanical allodynia in rat models of HIV-associated neuropathy, chemotherapy-induced peripheral neuropathy, and spinal nerve ligation-induced neuropathy, without effects on locomotion or anxiety. Thus, 5bk represents a novel T-type modulator that could be used to develop nonaddictive pain therapeutics.