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

Authors

Philip Walter Crawford, Marquette UniversityFollow
Peter Kovacic, University of Wisconsin - MilwaukeeFollow
Norman W. Gilman, Hoffman-LaRoche, Inc.
Michael D. Ryan, Marquette UniversityFollow

Document Type

Article

Language

eng

Format of Original

20 p.

Publication Date

12-1986

Publisher

Elsevier

Source Publication

Bioelectrochemistry and Bioenergetics

Source ISSN

0302-4598

Abstract

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; |U_p - U_p/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.

Comments

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

Recommended Citation

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.
https://epublications.marquette.edu/chem_fac/505