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 approximately 10 microM, whereas the dissociation constant between diphenhydramine and the resting channel is more than 300 microM. 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, approximately 110 degrees; center-center distance, approximately 5 A). 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.