title: Inhibitory effects of a new neuroprotective diltiazem analogue, T-477, on cloned brain Ca2+ channels expressed in Xenopus oocytes.
abstract: 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.
authors.affiliation: Institute of Molecular Pharmacology and Biophysics, University of Cincinnati College of Medicine, OH 45267-0828, USA. kobayasi@tanabe.co.jp
authors.forename: T
authors.initials: T
authors.lastname: Kobayashi
authors.forename: M
authors.initials: M
authors.lastname: Strobeck
authors.forename: A
authors.initials: A
authors.lastname: Schwartz
authors.forename: Y
authors.initials: Y
authors.lastname: Mori
mesh_terms: D000818:Animals; D001921:Brain / Q000187:drug effects* / Q000378:metabolism; D002121:Calcium Channel Blockers / Q000494:pharmacology*; D003001:Cloning, Molecular; D004110:Diltiazem / Q000494:pharmacology; D005260:Female; D066298:In Vitro Techniques; D017275:Isradipine / Q000494:pharmacology; D008564:Membrane Potentials / Q000187:drug effects; D018696:Neuroprotective Agents / Q000494:pharmacology*; D009865:Oocytes / Q000378:metabolism*; D018408:Patch-Clamp Techniques; D013843:Thiazines / Q000494:pharmacology*; D014981:Xenopus
chemical_list: D002121:Calcium Channel Blockers; D018696:Neuroprotective Agents; C108900:T 477; D013843:Thiazines; D004110:Diltiazem; D017275:Isradipine