title: Novel adamantane derivatives act as blockers of open ligand-gated channels and as anticonvulsants.
abstract: We examined the influence of the molecular structure of four novel adamantane derivatives on their ability to block the channels of nicotinic acetylcholine (ACh) and N-methyl-D-aspartate (NMDA) receptors. The structure of the drugs is Ad-CH2-N+H2-(CH2)5-R, where Ad is adamantane and R was varied from ammonium (IEM-1754) to tert-butyldimethylammonium (IEM-1857) radical. The compounds induced double-exponential decays of postsynaptic currents in frog muscles and flickering of NMDA-activated channels, suggesting that each drug acts as a fast open-channel blocker at both types of receptors. The equilibrium dissociation constants (Kd) of the drugs for ACh-activated channels at -80 mV were similar, whereas the Kd values for NMDA-activated channels at -80 mV were 2-10 times lower. Several observations suggested that occupation of either type of channel by these compounds inhibited channel closure; the time constant (tau) of the slow component of the decay of postsynaptic currents in the presence of each compound was greater than the control tau, the IC50 of IEM-1754 for inhibition of NMDA-activated whole-cell currents was > 20 times larger than its Kd for the open channel, and a transient increase in NMDA-activated whole-cell currents was observed after washout of IEM-1754. Thus, these drugs appear to act on nicotinic ACh and NMDA receptors via similar mechanisms, although the voltage dependence of block suggested that the drugs bind at a more superficial site in the ACh-activated channel. All compounds also potently prevented NMDA-induced convulsions in mice. The ED50 of IEM-1754 was 4 times lower than the ED50 of MK-801.
authors.affiliation: Department of Neuroscience, University of Pittsburgh, Pennsylvania 15260.
authors.forename: S M
authors.initials: SM
authors.lastname: Antonov
authors.forename: J W
authors.initials: JW
authors.lastname: Johnson
authors.forename: N Y
authors.initials: NY
authors.lastname: Lukomskaya
authors.forename: N N
authors.initials: NN
authors.lastname: Potapyeva
authors.forename: V E
authors.initials: VE
authors.lastname: Gmiro
authors.forename: L G
authors.initials: LG
authors.lastname: Magazanik
mesh_terms: D000218:Adamantane / Q000031:analogs & derivatives* / Q000378:metabolism / Q000494:pharmacology*; D000818:Animals; D000927:Anticonvulsants / Q000378:metabolism / Q000494:pharmacology*; D002799:Cholinergic Fibers / Q000187:drug effects / Q000502:physiology; D004594:Electrophysiology; D018691:Excitatory Amino Acid Antagonists / Q000494:pharmacology; D005260:Female; D066298:In Vitro Techniques; D015640:Ion Channel Gating / Q000187:drug effects*; D007473:Ion Channels / Q000187:drug effects* / Q000502:physiology; D007700:Kinetics; D008297:Male; D051379:Mice; D016202:N-Methylaspartate / Q000494:pharmacology; D009469:Neuromuscular Junction / Q000187:drug effects / Q000502:physiology; D011247:Pregnancy; D000644:Quaternary Ammonium Compounds / Q000378:metabolism / Q000494:pharmacology; D011896:Rana temporaria; D051381:Rats; D017207:Rats, Sprague-Dawley; D017470:Receptors, Glutamate / Q000187:drug effects / Q000378:metabolism; D016194:Receptors, N-Methyl-D-Aspartate / Q000037:antagonists & inhibitors* / Q000378:metabolism / Q000502:physiology; D011978:Receptors, Nicotinic / Q000378:metabolism / Q000502:physiology
chemical_list: D000927:Anticonvulsants; D018691:Excitatory Amino Acid Antagonists; C092754:IEM 1754; C118520:IEM 1857; D007473:Ion Channels; D000644:Quaternary Ammonium Compounds; D017470:Receptors, Glutamate; D016194:Receptors, N-Methyl-D-Aspartate; D011978:Receptors, Nicotinic; D016202:N-Methylaspartate; D000218:Adamantane