title: ZC88, a novel N-type calcium channel blocker from 4-amino-piperidine derivatives state-dependent inhibits Cav2.2 calcium channels.
abstract: Small molecular inhibitors of Cav2.2 have been reported for the treatment of neuropathic pain; however, low selectivity and side effects limit their further development. In our study, a series of new compounds were designed and synthesized by optimizing the 4-amino-piperidine template. The results show that ZC88 inhibits transiently expressed Cav2.2 in state-dependent manner in oocytes with an IC50 of 0.45 ± 0.09 μM. The steady-state inactivation relationship curve is shifted to more negative potentials for the calcium channels, suggesting that ZC88 blocks inactivated state of the channel. ZC88 does not present any remarkable effects on voltage-gated P/Q-type calcium channel currents, l-type calcium channel currents, potassium channel and sodium channel currents. Taken together, these in vitro data suggest that ZC88 is a voltage-dependent, subtype-selective Cav2.2 channel inhibitor and can achieve an improved therapeutic window over the relatively state-independent Cav2.2-selective inhibitor, which may have potential to be developed into a novel analgesic agent.
authors: Beijing Institute of Pharmacology and Toxicology, 27 Taiping Street, Beijing 100850, PR China.
authors: Shuzhuo
authors: S
authors: Zhang
authors: Chinese PLA General Hospital, 28 Fuxing Street, Beijing 100853, PR China.
authors: Lujia
authors: L
authors: Yang
authors: Beijing Institute of Pharmacology and Toxicology, 27 Taiping Street, Beijing 100850, PR China.
authors: Kang
authors: K
authors: Zhang
authors: Beijing Institute of Pharmacology and Toxicology, 27 Taiping Street, Beijing 100850, PR China.
authors: Xiaoyan
authors: X
authors: Liu
authors: Beijing Institute of Pharmacology and Toxicology, 27 Taiping Street, Beijing 100850, PR China.
authors: Weiwei
authors: W
authors: Dai
authors: Beijing Institute of Pharmacology and Toxicology, 27 Taiping Street, Beijing 100850, PR China.
authors: Cheng
authors: C
authors: Zhang
authors: Beijing Institute of Pharmacology and Toxicology, 27 Taiping Street, Beijing 100850, PR China.
authors: Zheng
authors: Z
authors: Yong
authors: Beijing Institute of Pharmacology and Toxicology, 27 Taiping Street, Beijing 100850, PR China. Electronic address: jinli9802@yahoo.com.
authors: Jin
authors: J
authors: Li
authors: Beijing Institute of Pharmacology and Toxicology, 27 Taiping Street, Beijing 100850, PR China. Electronic address: zhengjq@bmi.ac.cn.
authors: Jianquan
authors: J
authors: Zheng
mesh_terms: D018712:Analgesics, Non-Narcotic / Q000494:pharmacology; D000818:Animals; D002121:Calcium Channel Blockers / Q000494:pharmacology*; D020864:Calcium Channels, N-Type; D002478:Cells, Cultured; D005727:Ganglia, Spinal / Q000166:cytology / Q000187:drug effects / Q000378:metabolism; D006624:Hippocampus / Q000166:cytology / Q000187:drug effects / Q000378:metabolism; D006801:Humans; D008564:Membrane Potentials / Q000187:drug effects; D009474:Neurons / Q000166:cytology / Q000187:drug effects / Q000378:metabolism; D009865:Oocytes / Q000187:drug effects / Q000378:metabolism; D010880:Piperidines / Q000494:pharmacology*; D024642:Potassium Channels, Voltage-Gated / Q000378:metabolism; D011817:Rabbits; D051381:Rats; D017208:Rats, Wistar; D061566:Voltage-Gated Sodium Channels / Q000378:metabolism; D029867:Xenopus Proteins / Q000037:antagonists & inhibitors*; D014982:Xenopus laevis
chemical_list: D018712:Analgesics, Non-Narcotic; C527798:CACNA1B protein, Xenopus; D002121:Calcium Channel Blockers; D020864:Calcium Channels, N-Type; C531033:N-(1-(2,3-dimethoxyphenyl)-4-methyl-3-penten-1-yl)-1-(5-bromofurfuryl)-1-piperidyl-4-amine; D010880:Piperidines; D024642:Potassium Channels, Voltage-Gated; D061566:Voltage-Gated Sodium Channels; D029867:Xenopus Proteins
keywords: N-type calcium channel; Oocytes; Pain