INHIBITORY EFFECTS OF A NEW NEUROPROTECTIVE DILTIAZEM ANALOG, T-477, ON CLONED BRAIN CA2+ CHANNELS EXPRESSED IN XENOPUS OOCYTES

A new neuroprotective agent T-477 (( dihydro-4-diethlaminoacethyl-4H-1 -4-benzothiazine) and diltiazem are similar in chemical structures but they show different biological properties. To investigate the propert ies that differentiate T-477 from diltiazem, we examined the effects o f the compounds on a cardiac L-type and brain non-L-type Ca2+ channels expressed in Xenopus oocytes. Cardiac L-type currents were inhibited by Ca2+ channel antagonists with an order of potency: PN200-110 isradi pine much greater than diltiazem > T-477. Brain BI (class A)-, BII (cl ass E)- and BIII (class B)-type Ca2+ channel currents were inhibited b y T-477 with an IC50 of 45, 74 and 59 mu M, respectively, whereas dilt iazem barely inhibited the brain non-L-type channels and PN200-110 had no effect. T-477 caused a marked use-and frequency-dependent block of BI Ca2+ channel currents, as demonstrated by a cumulative increase of the block during a train of depolarizing pulses, which seemed to be d ue to a slow repriming of the drug-bound channels from inactivation. T hese results suggest that T-477 exerts neuroprotection of brain neuron s from ischemic neuronal damage through its inhibitory action on brain Ca2+ channels that differentiates T-477 from cardiac L-type channel b lockers such as diltiazem and PN200-110. (C) 1997 Elsevier Science B.V .