1. ¹Department of Pharmacology, Faculty of Pharmacy, University of Belgrade, Belgrade, Serbia
2. ²Department of Chemistry and Biochemistry, University of Wisconsin-Milwaukee, Milwaukee, WI, USA
3. ³Center for Brain Research, Medical University Vienna, Vienna, Austria
4. ⁴Department of Pharmacology, Medical Faculty, University of Belgrade, Belgrade, Serbia
5. ⁵National Poison Center, Military Medical Academy, Belgrade, Serbia

Correspondence: Dr MM Savi, Department of Pharmacology, Faculty of Pharmacy, University of Belgrade, Vojvode Stepe 450, Belgrade 11221, Serbia. Tel: +381 11 3970379 ext. 680; Fax: +381 11 3972840; E-mail: miroslav@pharmacy.bg.ac.yu

Received 3 November 2006; Revised 15 February 2007; Accepted 23 February 2007; Published online 28 March 2007.

Abstract

Classical benzodiazepines (BZs) exert anxiolytic, sedative, hypnotic, muscle relaxant, anticonvulsive, and amnesic effects through potentiation of neurotransmission at GABA_A receptors containing ₁, ₂, ₃ or ₅ subunits. Genetic studies suggest that modulation at the ₁ subunit contributes to much of the adverse effects of BZs, most notably sedation, ataxia, and amnesia. Hence, BZ site ligands functionally inactive at GABA_A receptors containing the ₁ subunit are considered to be promising leads for novel, anxioselective anxiolytics devoid of sedative properties. In pursuing this approach, we used two-electrode voltage clamp experiments in Xenopus oocytes expressing recombinant GABA_A receptor subtypes to investigate functional selectivity of three newly synthesized BZ site ligands and also compared their in vivo behavioral profiles. The compounds were functionally selective for ₂-, ₃-, and ₅-containing subtypes of GABA_A receptors (SH-053-S-CH3 and SH-053-S-CH3-2'F) or essentially selective for ₅ subtypes (SH-053-R-CH3). Possible influences on behavioral measures were tested in the elevated plus maze, spontaneous locomotor activity, and rotarod test, which are considered primarily predictive of the anxiolytic, sedative, and ataxic influence of BZs, respectively. The results confirmed the substantially diminished ataxic potential of BZ site agonists devoid of ₁ subunit-mediated effects, with preserved anti-anxiety effects at 30 mg/kg of SH-053-S-CH3 and SH-053-S-CH3-2'F. However, all three ligands, dosed at 30 mg/kg, decreased spontaneous locomotor activity, suggesting that sedation may be partly dependent on activity mediated by ₅-containing GABA_A receptors. Hence, it could be of importance to avoid substantial agonist activity at ₅ receptors by candidate anxioselective anxiolytics, if clinical sedation is to be avoided.