Modulation of GABAA receptor-mediated currents by derivatives of benzophenone

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University of Central Lancashire / University of Liverpool (2002) J Physiol 543P, S085

Communications: Modulation of GABAA receptor-mediated currents by derivatives of benzophenone

M.V. Kopanitsa*, L.M. Yakubovska†, O.P. Rudenko‡ and O.A. Krishtal*

*Department of Cellular Membranology, Bogomoletz Institute of Physiology, Kyiv 01024, Ukraine, †Department of Chemistry of Biologically Active Substances, Bogatsky Physico-Chemical Institute, Odessa 65080, Ukraine and ‡Laboratory of Synthesis of Medicinal Preparations (PNIL-5), Mechnikov Odessa National University, Odessa 65058, Ukraine

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Derivatives of benzophenone occur in blood as physiological metabolites of 1,4-benzodiazepines. Some of them were shown to modulate the amplitude and time course of currents mediated by activation of GABAA receptors (Kopanitsa et al. 2001; Kopanitsa & Rudenko, 2002). Here we have investigated the mechanism of this modulation on the example of 5-bromo-2â-chloro-2-aminobenzophenone (BZP1), a metabolite of phenazepam, and the relationship between the chemical structure and extent of modulation of GABAA receptors among several other derivatives of benzophenone.

Whole-cell voltage-clamp recordings were obtained from individual Purkinje neurones enzymatically isolated from rat cerebellar slices (11- to 14-day-old animals rapidly decapitated according to the Institute’s regulations). Drug-containing solutions were applied by the ‘concentration-clamp method’. BZP1 caused dual modification of peak amplitudes of GABA-gated currents that depended upon the concentration of applied GABA and incubation time. Following short 10 s pre-incubations, 1Ð30 mM BZP1 facilitated activation and delayed deactivation of currents evoked by 500 ms pulses of 20 mM GABA. In addition, 10 mM BZP1 prominently enhanced biexponential desensitisation of currents during applications of 500 mM GABA mainly by decreasing the value of the fast time constant of the desensitisation. Continuous 6 min incubation with 10 mM BZP1 during GABA stimulation or its administration between but not during 1 s pulses of 500 mM GABA led to a gradual, partly reversible attenuation of GABA-activated currents. This inhibition was not observed when BZP1 was applied only during pulses of GABA, indicating that the blockade was not use dependent.

At concentrations of 10 mM, several 5-substituted benzophenones, but not 2-aminobenzophenone or benzophenone itself exhibited modulatory properties similar to BZP1 (accelerated activation and desensitisation, decelerated deactivation of GABA-activated currents) and distinct from those of picrotoxin (10-30 mM) and benzylpenicillin (500 mM). Therefore, we conclude that derivatives of benzophenone are a novel class of GABAA receptor modulators with unique pharmacological profile.

This work was supported by INTAS, The Wellcome Trust and HHMI.

All procedures accord with current local guidelines.

Where applicable, experiments conform with Society ethical requirements.

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