Modulation of GABA(A) receptor-mediated currents by benzophenone derivatives in isolated rat Purkinje neurones.

We investigated modulation of GABA(A) receptor-mediated whole-cell currents in cerebellar Purkinje neurones by several derivatives of benzophenone. A metabolite of phenazepam, 5-bromo-2'-chloro-2-aminobenzophenone (I), 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, 1-30 microM I facilitated activation and delayed deactivation of currents evoked by 500 ms pulses of 20 microM GABA. In addition, 10 microM I prominently enhanced desensitisation of currents during applications of 500 microM GABA mainly by decreasing the value of the fast time constant of the desensitisation. Continuous 6 min incubation with 10 microM I during GABA stimulation or its administration between but not during 1 s pulses of 500 microM GABA led to a gradual, partly reversible attenuation of GABA-activated currents. This inhibition was not observed when I was applied only during pulses of GABA, indicating that the blockade was not use-dependent. One of the possible mechanisms of this down-modulation could be an intracellular effect of I, because when applied intracellularly it caused slow inhibition of responses to consecutive GABA pulses. When 3-30 microM I was applied on the background of small 'plateau'-like current 5-7 s after application of 500 microM GABA, it was able to block open channels with on and off rates similar to those observed with 30 microM picrotoxin but much slower than in the case of 500 microM benzylpenicillin. At a concentration of 10 microM, 5-substituted benzophenones, but not 2-aminobenzophenone or benzophenone itself, exhibited modulatory properties similar to I and distinct from those of picrotoxin and benzylpenicillin. Therefore, we conclude that derivatives of benzophenone are a novel class of GABA(A) receptor modulators with a unique pharmacological profile.

[Distribution of the 14C-hydrated analog of phenazepam in the organs and tissues of mice]. / Raspredelenie 14C-gidrirovannogo analoga fenazepama v nekotorykh organakh i tkaniakh myshei.

The absorption kinetics of hydrated phenazepam analog into the liver, spleen, brain, kidney, blood, lungs, heart, skeletal and fat tissues is studied at 0.25-24 hour intervals after its intraperitoneal (i/p) administration to mice. Drug concentration in the above mentioned organs was maximal 0.5-1 hour later. The decrease of the drug and its metabolite level in the organs under study is a biexponential process, consisting of "quick" (1-6 hours) and "slow" phases. The rate of absorption of hydrated phenazepam analog into the organs and tissues and its elimination is lower than that of phenanzepam.