A new type of Ca2+ channel blocker, NC-1100, inhibits the low- and high-threshold Ca2+ currents in the rat CNS neurons.
The effect of a new type of organic Ca2+ channel blocker, NC-1100 [(+/-)-1-(3,4-dimethoxyphenyl)-2-(4-diphenylmethylpiperazinyl)etha nol dihydrochloride], on both low- and high-threshold Ca2+ currents was studied in the whole-cell mode of the pyramidal neurons freshly dissociated from rat hippocampal CA1 region under voltage-clamp condition. The NC-1100 reversibly reduced the high-threshold Ca2+ current (HVA ICa) in a concentration-dependent manner without affecting the current-voltage relationship. The values of half-inhibition (IC50) were 1.3 x 10(-5) and 9.1 x 10(-6) M in external solution containing 10 and 2.5 mM Ca2+, respectively. The NC-1100 also decreased the low-threshold Ca2+ current (LVA ICa) in a concentration-dependent manner. The inhibitory potency was augmented by increasing the stimulation frequency and/or decreasing the extracellular Ca2+ concentration to a physiological range (2.5 mM). The IC50 value decreased to 7.7 x 10(-7) M in external solution containing 2.5 mM Ca2+ at a stimulation frequency of 1 Hz. The NC-1100 delayed the reactivation of LVA Ca2+ channel and enhanced voltage-dependently the steady-state inactivation, suggesting that this drug bound not only the resting LVA Ca2+ channel but also the inactivated one.
Miyake
N
N
Laboratory of Pharmacology, Nippon Chemiphar Co. Ltd., Misato, Japan.
Wakamori
M
M
Akaike
N
N
D000818:Animals; D002121:Calcium Channel Blockers / Q000494:pharmacology*; D006624:Hippocampus / Q000166:cytology / Q000187:drug effects*; D009474:Neurons / Q000187:drug effects*; D010879:Piperazines / Q000494:pharmacology*; D051381:Rats; D017208:Rats, Wistar
D002121:Calcium Channel Blockers; D010879:Piperazines; C050134:tamolarizine