Charge Transfer Mechanism for Benzodiazepine (BZ) Action: Correlation of Reduction Potential of BZ Iminium with Structure and Drug Activity
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Bioelectrochemistry and Bioenergetics
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.
Crawford, Philip Walter; Kovacic, Peter; Gilman, Norman W.; and Ryan, Michael D., "Charge Transfer Mechanism for Benzodiazepine (BZ) Action: Correlation of Reduction Potential of BZ Iminium with Structure and Drug Activity" (1986). Chemistry Faculty Research and Publications. 505.