title: New CNS-specific calcium antagonists.
abstract: Ischemic insults to the brain in stroke or traumatic brain injury produce excessive release of glutamate from depolarized nerve terminals. This excessive glutamate release in turn stimulates massive calcium entry into nerve cells, activating a biochemical cascade that results in cell death. A major pathway of calcium entry into depolarized nerve cells is through voltage-sensitive, high threshold calcium channels. A large fraction of this calcium entry is mediated through "R-type" calcium channels, channels resistant to blockage by dihydropyridine calcium antagonists such as nimodipine. A newly discovered compound derived from spider venom, CNS 2103, antagonizes both R-type channels and dihydropyridine-sensitive ("L-type") calcium channels. This broad spectrum of action, coupled with selectivity for calcium channels over other classes of voltage-sensitive and ligand-gated ion channels, makes CNS 2103 an interesting lead for development of drugs to treat ischemic brain injury. Activation of presynaptic ("N-type") calcium channels in nerve terminals is a primary cause of excessive neurotransmitter release in brain ischemia. Prevention of glutamate release by blockade of N-type channels in glutamatergic nerve terminals may, at an early stage in the pathophysiological cascade, abort the process leading to nerve cell death. Cambridge NeuroScience has developed a novel rapid kinetic approach for monitoring glutamate release from brain nerve terminals in vitro, and this has led to CNS 1145, a substituted guanidine that selectively blocks a kinetic component of calcium-dependent glutamate release mediated by persistent depolarization. Additional evidence suggests that CNS 1145 antagonizes presynaptic N-type calcium channels, and this may account at least in part for its ability to block glutamate release.
authors.affiliation: Cambridge NeuroScience, Inc., Massachusetts.
authors.forename: R N
authors.initials: RN
authors.lastname: McBurney
authors.forename: D
authors.initials: D
authors.lastname: Daly
authors.forename: J B
authors.initials: JB
authors.lastname: Fischer
authors.forename: L Y
authors.initials: LY
authors.lastname: Hu
authors.forename: K
authors.initials: K
authors.lastname: Subbarao
authors.forename: A G
authors.initials: AG
authors.lastname: Knapp
authors.forename: K
authors.initials: K
authors.lastname: Kobayashi
authors.forename: L
authors.initials: L
authors.lastname: Margolin
authors.forename: N L
authors.initials: NL
authors.lastname: Reddy
authors.forename: S M
authors.initials: SM
authors.lastname: Goldin
mesh_terms: D000818:Animals; D001930:Brain Injuries / Q000188:drug therapy* / Q000503:physiopathology; D002545:Brain Ischemia / Q000188:drug therapy* / Q000503:physiopathology; D002118:Calcium / Q000378:metabolism*; D002121:Calcium Channel Blockers / Q000627:therapeutic use*; D015220:Calcium Channels / Q000187:drug effects / Q000502:physiology*; D016923:Cell Death; D002490:Central Nervous System / Q000502:physiology*; D002561:Cerebrovascular Disorders / Q000188:drug therapy* / Q000503:physiopathology; D006801:Humans; D009474:Neurons / Q000166:cytology / Q000473:pathology / Q000502:physiology*; D013569:Synapses / Q000187:drug effects / Q000502:physiology
chemical_list: D002121:Calcium Channel Blockers; D015220:Calcium Channels; D002118:Calcium