TY - JOUR
T1 - Inhibition of Na+ current by diphenhydramine and other diphenyl compounds
T2 - Molecular determinants of selective binding to the inactivated channels
AU - Kuo, Chung Chin
AU - Huang, Ron Chi
AU - Lou, Bih Show
PY - 2000
Y1 - 2000
N2 - Diphenhydramine is an H1 histamine receptor antagonist, yet it also has a clinically useful local anesthetic effect. We found that diphenhydramine inhibits the neuronal Na+ current, and the inhibition is stronger with more positive holding potentials. The dissociation constant between diphenhydramine and the inactivated Na+ channel is ~10 μM, whereas the dissociation constant between diphenhydramine and the resting channel is more than 300 μM. The local anesthetic effect of diphenhydramine thus is ascribable to inhibition of Na+ current by selective binding of the drug to the inactivated channels. Most interestingly, many other compounds, such as the anti-inflammatory drug diclofenac, the anticonvulsant drug phenytoin, the antidepressant drug imipramine, and the anticholinergic drug benztropine, have similar effects on neuronal Na+ current. There is no apparent common motif in the chemical structure of these compounds, except that they all contain two phenyl groups. Molecular modeling further shows that the two benzene rings in all these drugs have very similar spatial orientations (stem bond angle, ~110 degrees; center-center distance, ~5 Å). In contrast, the two phenyl groups in phenylbutazone, a drug that has only a slight effect on Na+ current, are oriented in quite a different way. These findings strongly suggest that the two phenyl groups are the key ligands interacting with the channel. Because the binding counterpart of a benzene ring usually is also a benzene ring, some aromatic side chain groups of the Na+ channel presumably are realigned during the gating process to make the very different affinity to the aforementioned drugs between the inactivated and the resting channels.
AB - Diphenhydramine is an H1 histamine receptor antagonist, yet it also has a clinically useful local anesthetic effect. We found that diphenhydramine inhibits the neuronal Na+ current, and the inhibition is stronger with more positive holding potentials. The dissociation constant between diphenhydramine and the inactivated Na+ channel is ~10 μM, whereas the dissociation constant between diphenhydramine and the resting channel is more than 300 μM. The local anesthetic effect of diphenhydramine thus is ascribable to inhibition of Na+ current by selective binding of the drug to the inactivated channels. Most interestingly, many other compounds, such as the anti-inflammatory drug diclofenac, the anticonvulsant drug phenytoin, the antidepressant drug imipramine, and the anticholinergic drug benztropine, have similar effects on neuronal Na+ current. There is no apparent common motif in the chemical structure of these compounds, except that they all contain two phenyl groups. Molecular modeling further shows that the two benzene rings in all these drugs have very similar spatial orientations (stem bond angle, ~110 degrees; center-center distance, ~5 Å). In contrast, the two phenyl groups in phenylbutazone, a drug that has only a slight effect on Na+ current, are oriented in quite a different way. These findings strongly suggest that the two phenyl groups are the key ligands interacting with the channel. Because the binding counterpart of a benzene ring usually is also a benzene ring, some aromatic side chain groups of the Na+ channel presumably are realigned during the gating process to make the very different affinity to the aforementioned drugs between the inactivated and the resting channels.
UR - http://www.scopus.com/inward/record.url?scp=0033976628&partnerID=8YFLogxK
M3 - 文章
C2 - 10617688
AN - SCOPUS:0033976628
SN - 0026-895X
VL - 57
SP - 135
EP - 143
JO - Molecular Pharmacology
JF - Molecular Pharmacology
IS - 1
ER -