The structure-activity relationship study on 2-, 5-, and 6-position of the water soluble 1,4-dihydropyridine derivatives blocking N-type calcium channels.

In order to find an injectable and selective N-type calcium channel blocker, we have performed the structure-activity relationship (SAR) study on the 2-, 5-, and 6-position of 1,4-dihydropyridine-3-carboxylate derivative APJ2708 (2), which is a derivative of Cilnidipine and has L/N-type calcium channel dual inhibitory activities. As a consequence of the optimization, 6-dimethylacetal derivative 7 was found to have an effective inhibitory activity against N-type calcium channels with more than 170-fold lower activity for L-type channel compared to that of APJ2708.

Discovery, structure-activity relationship study, and oral analgesic efficacy of cyproheptadine derivatives possessing N-type calcium channel inhibitory activity.

Antiallergic drug cyproheptadine (Cyp) is known to have inhibitory activities for L-type calcium channels in addition to histamine and serotonin receptors. Since we found that Cyp had an inhibitory activity against N-type calcium channel, Cyp was optimized to obtain more selective N-type calcium channel blocker with analgesic action. As a consequence of the optimization, we found 13 with potent N-type calcium channel inhibitory activity which had lower inhibitory activities against L-type calcium channel, histamine (H1), and serotonin (5-HT2A) receptors than those of Cyp. 13 showed an oral analgesic activity in rat formalin-induced pain model.

Structure-activity relationship study of 1,4-dihydropyridine derivatives blocking N-type calcium channels.

Cilnidipine is a 1,4-dihydropyridine derived L/N-type calcium channel dual blocker possessing neuroprotective and analgesic effects which are related to its N-type calcium channel inhibitory activity. In order to find specific N-type calcium channel blockers with the least effects on cardiovascular system, we performed structure-activity relationship study on APJ2708, which is a derivative of cilnidipine, and found a promising N-type calcium channel blocker 21b possessing analgesic effect in vivo with a 1600-fold lower activity against L-type calcium channels than that of cilnidipine.

Neuronal Ca2+ channel blocking action of an antihypertensive drug, cilnidipine, in IMR-32 human neuroblastoma cells.

Although the anti-sympathetic mechanisms of the antihypertensive drug cilnidipine have been analyzed in neuronal cells derived from rodents, there is little information regarding the effects of cilnidipine in human neuronal cells. We investigated the effects of cilnidipine on N-type Ca2+ channels in IMR-32 human neuroblastoma cells using fura-2-based microfluorimetry. The ratio of the intensities of the emitted fluorescence at an excitation wavelength of 340 nm to that at 380 nm was calibrated to estimate the intracellular concentration of Ca2+. Stimulation of IMR-32 cells by 40 mmol/l KCl immediately increased the intensities ratio. In the presence of 10 micromol/l of nifedipine to block L-type Ca2+ channels, omega-conotoxin GVIA, a selective N-type Ca2+ channel blocker, in a concentration of 1 micromol/l suppressed the elevation of the intensities ratio induced by 40 mmol/l KCl. Similarly, cilnidipine in a concentration of 10 micromo/l suppressed the elevation of the ratio induced by 40 mmol/l KCl, and this suppression was effectively inhibited after the treatment with omega-conotoxin GVIA. These results suggest that cilnidipine potentially inhibits N-type Ca2+ channels in human neuronal cells and might be applied as a prospective therapeutic tool to provide neuronal protection as well as its antihypertensive effects and anti-sympathetic actions.