title: NGP1-01 is a brain-permeable dual blocker of neuronal voltage- and ligand-operated calcium channels.
abstract: Calcium overload of neurons leads to cell death and is a key feature in neurodegenerative diseases. The polycyclic amine NGP1-01 blocks L-type voltage operated calcium channels in cardiomyocytes. Here, we tested whether NGP1-01 blocks neuronal calcium channels. NGP1-01 (1 microM) inhibited depolarization-induced calcium influx by 78% in cortical neurons preloaded with fura-2 AM, with a potency similar to nimodipine. NGP1-01 (1 microM) also inhibited N-methyl-D: -aspartate (NMDA)-induced (1 mM) calcium influx by 52%, only slightly less potent than memantine. Using in vivo-microdialysis, we monitored choline release during NMDA infusion as a measure of excitotoxic membrane breakdown. Intraperitoneal injection of NGP1-01 (40 mg/kg) reduced NMDA-induced membrane breakdown by 31% (P < 0.01) while memantine (10 mg/kg) reduced choline release by 40%. Our results demonstrate that NGP1-01 simultaneously blocks both major neuronal calcium channels and is sufficiently brain-permeable. We conclude that NGP1-01 is a promising lead structure for a new class of dual-mechanism neuroprotective agents.
authors.affiliation: Department of Pharmaceutical Sciences, Texas Tech School of Pharmacy, Amarillo, TX 79106, USA.
authors.forename: Cornelia
authors.initials: C
authors.lastname: Kiewert
authors.forename: Joachim
authors.initials: J
authors.lastname: Hartmann
authors.forename: James
authors.initials: J
authors.lastname: Stoll
authors.forename: Thomas J
authors.initials: TJ
authors.lastname: Thekkumkara
authors.forename: Cornelis J
authors.initials: CJ
authors.lastname: Van der Schyf
authors.forename: Jochen
authors.initials: J
authors.lastname: Klein
mesh_terms: D000818:Animals; D001952:Bridged-Ring Compounds / Q000493:pharmacokinetics / Q000494:pharmacology*; D002118:Calcium / Q000378:metabolism; D002121:Calcium Channel Blockers / Q000493:pharmacokinetics / Q000494:pharmacology*; D015220:Calcium Channels / Q000187:drug effects* / Q000502:physiology; D002478:Cells, Cultured; D002540:Cerebral Cortex / Q000378:metabolism*; D002794:Choline / Q000378:metabolism; D018690:Excitatory Amino Acid Agonists / Q000494:pharmacology; D015640:Ion Channel Gating; D008024:Ligands; D017551:Microdialysis; D016202:N-Methylaspartate / Q000494:pharmacology; D009474:Neurons / Q000187:drug effects* / Q000502:physiology; D010539:Permeability; D051381:Rats; D017207:Rats, Sprague-Dawley
chemical_list: D001952:Bridged-Ring Compounds; D002121:Calcium Channel Blockers; D015220:Calcium Channels; D018690:Excitatory Amino Acid Agonists; D008024:Ligands; C049649:NGP 1-01; D016202:N-Methylaspartate; D002794:Choline; D002118:Calcium