Inhibitory effects of a new neuroprotective diltiazem analogue, T-477, on cloned brain Ca2+ channels expressed in Xenopus oocytes.

A new neuroprotective agent T-477 ((R)-(+)-2-(4-chlorophenyl)-2,3-dihydro-4-diethylaminoacetyl-4H-1, 4-benzothiazine) and diltiazem are similar in chemical structures but they show different biological properties. To investigate the properties that differentiate T-477 from diltiazem, we examined the effects of 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 isradipine > > diltiazem > T-477. Brain BI (class A)-, BII (class E)- and BIII (class B)-type Ca2+ channel currents were inhibited by T-477 with an IC50 of 45, 74 and 59 microM, respectively, whereas diltiazem 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 due to a slow repriming of the drug-bound channels from inactivation. These results suggest that T-477 exerts neuroprotection of brain neurons from ischemic neuronal damage through its inhibitory action on brain Ca2+ channels that differentiates T-477 from cardiac L-type channel blockers such as diltiazem and PN200-110.