AJ-2615, a long-acting Ca2+ channel antagonist with a novel structure.
AJ-2615, a dihydrodibenzothiepin derivative, at 10(-4) M inhibited the peak ICa amplitude of an identifiable Achatina neurone, PON (periodically oscillating neurone), by nearly a half of the control response 30 min after the start of perfusion (ED50: 0.96 x 10(-4) M). The ICa inhibition was still sustained 30 min after washout, indicating that AJ-2615 has long-lasting activity. The compound inhibited the ICa over a wide range of membrane potentials depolarized by the voltage pulse (Vd), but did not change the membrane potential required to produce the maximal ICa (Vd = 0 mV). The additional decrease in ICa amplitude caused by changing from low-frequency (1/5 min) depolarizing pulses to high-frequency (3/min) depolarizing pulses in the presence of AJ-2615 at 10(-4) M was 39.2 +/- 4.5% (mean+S.E.M.; n = 5), indicating use dependence. The steady state inactivation curves were measured in the presence or absence of AJ-2615 at 10(-4) M with a depolarizing prepulse (Vd = varied, duration = 30 s) followed by a depolarizing test pulse (Vd = +10 mV, duration 80 ms), with 2 ms intervals (n = 3): the ratio of AJ-2615 dissociation constant in the resting Ca2+ channel (Kr) and in the inactivated Ca2+ channel (Ki), Kr/Ki, was calculated to be 9.6:1, indicating voltage dependence.
Liu
G J
GJ
Department of Physiology, Gifu University School of Medicine, Japan.
Takeuchi
H
H
D000818:Animals; D002121:Calcium Channel Blockers / Q000737:chemistry / Q000494:pharmacology*; D003988:Dibenzothiepins / Q000737:chemistry / Q000494:pharmacology*; D066298:In Vitro Techniques; D008564:Membrane Potentials / Q000187:drug effects; D015394:Molecular Structure; D009474:Neurons / Q000187:drug effects*; D010879:Piperazines / Q000737:chemistry / Q000494:pharmacology; D012908:Snails / Q000187:drug effects*
D002121:Calcium Channel Blockers; D003988:Dibenzothiepins; D010879:Piperazines; C067818:monatepil