MolPharm

Home Help [Feedback] [For Subscribers] [Archive] [Search] [Contents]
QUICK SEARCH:   [advanced]


     

This Article
Right arrow Full Text (PDF)
Right arrow Submit a response
Right arrow Alert me when this article is cited
Right arrow Alert me when eLetters are posted
Right arrow Alert me if a correction is posted
Services
Right arrow Similar articles in this journal
Right arrow Similar articles in PubMed
Right arrow Alert me to new issues of the journal
Right arrow Download to citation manager
Citing Articles
Right arrow Citing Articles via HighWire
Right arrow Citing Articles via Google Scholar
Google Scholar
Right arrow Articles by Antonov, S. M.
Right arrow Articles by Magazanik, L. G.
Right arrow Search for Related Content
PubMed
Right arrow PubMed Citation
Right arrow Articles by Antonov, S. M.
Right arrow Articles by Magazanik, L. G.

Novel adamantane derivatives act as blockers of open ligand-gated channels and as anticonvulsants

SM Antonov, JW Johnson, NY Lukomskaya, NN Potapyeva, VE Gmiro and LG Magazanik

Department of Neuroscience, University of Pittsburgh, Pennsylvania 15260.

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.

Volume 47, Issue 3, pp. 558-567, 03/01/1995
Copyright © 1995 by American Society for Pharmacology and Experimental Therapeutics




This article has been cited by other articles:


Home page
 J. Neurosci.Home page
A. I. Sobolevsky, S. G. Koshelev, and B. I. Khodorov
Probing of NMDA Channels with Fast Blockers
J. Neurosci., December 15, 1999; 19(24): 10611 - 10626.
[Abstract] [Full Text] [PDF]

Home page
 J. Pharmacol. Exp. Ther.Home page
M. Grauert, J. M. Rho, S. Subramaniam, and M. A. Rogawski
N-Methyl-D-aspartate Receptor Channel Block by the Enantiomeric 6,7-Benzomorphans BIII 277 CL and BIII 281 CL
J. Pharmacol. Exp. Ther., May 1, 1998; 285(2): 767 - 776.
[Abstract] [Full Text]

Home page
 J. Neurophysiol.Home page
T. A. Blanpied, F. A. Boeckman, E. Aizenman, and J. W. Johnson
Trapping Channel Block of NMDA-Activated Responses By Amantadine and Memantine
J Neurophysiol, January 1, 1997; 77(1): 309 - 323.
[Abstract] [Full Text] [PDF]


Home Help [Feedback] [For Subscribers] [Archive] [Search] [Contents]
All ASPET Journals Molecular Pharmacology Pharmacological Reviews
Molecular Interventions Drug Metabolism and Disposition

Copyright © 1995 by the American Society for Pharmacology and Experimental Therapeutics