Selection of 2′-Fluoro-modified RNA Aptamers for Alleviation of Cocaine and MK-801Inhibition of the Nicotinic Acetylcholine Receptor

Selection of 2′-Fluoro-modified RNA Aptamers for Alleviation of Cocaine and MK-801Inhibition of... The nicotinic acetylcholine receptor (nAChR) belongs to a group of five stracturally related proteins that regulate signal transmission between approximately 1012 cells of the mammalian nervous system. Many therapeutic agents and abused drugs inhibit the nAChR, including the anti-convulsant MK-801 and the abused drug cocaine. Many attempts have been made to find compounds that prevent inhibition by cocaine. Use of transient kinetic techniques to investigate the inhibition of the receptor by MK-801 and cocaine led to an inhibition mechanism not previously proposed. The mechanism led to the development of combinatorially synthesized RNA ligands that alleviate inhibition of the receptor. However, these ligands are relatively unstable. Here we determined whether much more stable 2′-fluoro-modified RNA ligands can be prepared and used to study the alleviation of receptor inhibition. Two classes of 2′-fluoro-modified RNA ligands were obtained: One class binds with higher affinity to the cocaine-binding site on the closed-channel form and, as predicted by the mechanism, inhibits the receptor. The second class binds with equal or higher affinity to the cocaine-binding site on the open-channel form and, as predicted by the mechanism, does not inhibit the receptor, and does alleviate cocaine and MK-801 inhibition of the nAChR. The stability of these 2′-fluoro-RNAs expands the utility of these ligands. http://www.deepdyve.com/assets/images/DeepDyve-Logo-lg.png The Journal of Membrane Biology Springer Journals

Selection of 2′-Fluoro-modified RNA Aptamers for Alleviation of Cocaine and MK-801Inhibition of the Nicotinic Acetylcholine Receptor

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Publisher
Springer-Verlag
Copyright
Copyright © 2004 by Springer Science+Business Media, Inc.
Subject
Life Sciences; Human Physiology; Biochemistry, general
ISSN
0022-2631
eISSN
1432-1424
D.O.I.
10.1007/s00232-004-0725-4
Publisher site
See Article on Publisher Site

Abstract

The nicotinic acetylcholine receptor (nAChR) belongs to a group of five stracturally related proteins that regulate signal transmission between approximately 1012 cells of the mammalian nervous system. Many therapeutic agents and abused drugs inhibit the nAChR, including the anti-convulsant MK-801 and the abused drug cocaine. Many attempts have been made to find compounds that prevent inhibition by cocaine. Use of transient kinetic techniques to investigate the inhibition of the receptor by MK-801 and cocaine led to an inhibition mechanism not previously proposed. The mechanism led to the development of combinatorially synthesized RNA ligands that alleviate inhibition of the receptor. However, these ligands are relatively unstable. Here we determined whether much more stable 2′-fluoro-modified RNA ligands can be prepared and used to study the alleviation of receptor inhibition. Two classes of 2′-fluoro-modified RNA ligands were obtained: One class binds with higher affinity to the cocaine-binding site on the closed-channel form and, as predicted by the mechanism, inhibits the receptor. The second class binds with equal or higher affinity to the cocaine-binding site on the open-channel form and, as predicted by the mechanism, does not inhibit the receptor, and does alleviate cocaine and MK-801 inhibition of the nAChR. The stability of these 2′-fluoro-RNAs expands the utility of these ligands.

Journal

The Journal of Membrane BiologySpringer Journals

Published: Jan 1, 2004

References

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