Charge Transfer Mechanism for Benzodiazepine (BZ) Action: Correlation of Reduction Potential of BZ Iminium with Structure and Drug Activity

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20 p.

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Bioelectrochemistry and Bioenergetics

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A novel mechanism for BZ action is proposed in which a BZ is protonated by GABA or protein RNH3+ to yield an iminium species that is responsible for drug activity viacharge transfer (c.t.). The following evidence from our work and prior studies supports this concept:

•binding sites for BZs and GABA are apparently on the same protein complex; data point to possible interaction between the two ligands;
•recent theoretical studies propose reaction of basic imine of BZ with cationic RNH3+ of protein at the receptor site;
•BZ is protonated by weak acids, such as acetic and GABA, to give iminium ions which exhibit appreciable and favorable increases in reduction potential in vitro;
•the reduction potentials are of the same order of magnitude as for a number of other biologically active compounds;
•reversible electron uptake has been shown to occur with some protonated BZ drugs; |Up - Up/2| calculations from the voltammograms of some BZs indicate the potential for reversible electrochemical processes;
•correlations exist involving reduction potential of BZ iminium, structure, and drug activity;
•a significant number of BZ agonists, inverse agonists, and antagonists incorporate the imine-type precursor of iminium;
•the postulated c.t. pathway is in keeping with a variety of bioelectrochemical phenomena arising from active site binding.


Bioelectrochemistry and Bioenegetics, Vol. 16, No. 4 (1986): 407-426. DOI.