GABAA receptor modulation by piperine and a non-TRPV1 activating derivative.

The action of piperine (the pungent component of pepper) and its derivative SCT-66 ((2E,4E)-5-(1,3-benzodioxol-5-yl))-N,N-diisobutyl-2,4-pentadienamide) on different gamma-aminobutyric acid (GABA) type A (GABA(A)) receptors, transient-receptor-potential-vanilloid-1 (TRPV1) receptors and behavioural effects were investigated. GABA(A) receptor subtypes and TRPV1 receptors were expressed in Xenopus laevis oocytes. Modulation of GABA-induced chloride currents (I(GABA)) by piperine and SCT-66 and activation of TRPV1 was studied using the two-microelectrode-voltage-clamp technique and fast perfusion. Their effects on explorative behaviour, thermoregulation and seizure threshold were analysed in mice. Piperine acted with similar potency on all GABA(A) receptor subtypes (EC₅₀ range: 42.8±7.6 μM (α₂β₂)-59.6±12.3 μM (α₃β₂). I(GABA) modulation by piperine did not require the presence of a γ(2S)-subunit, suggesting a binding site involving only α and β subunits. I(GABA) activation was slightly more efficacious on receptors formed from β(2/3) subunits (maximal I(GABA) stimulation through α₁β₃ receptors: 332±64% and α₁β₂: 271±36% vs. α₁β₁: 171±22%, p<0.05) and α₃-subunits (α₃β₂: 375±51% vs. α₅β₂:136±22%, p<0.05). Replacing the piperidine ring by a N,N-diisobutyl residue (SCT-66) prevents interactions with TRPV1 and simultaneously increases the potency and efficiency of GABA(A) receptor modulation. SCT-66 displayed greater efficacy on GABA(A) receptors than piperine, with different subunit-dependence. Both compounds induced anxiolytic, anticonvulsant effects and reduced locomotor activity; however, SCT-66 induced stronger anxiolysis without decreasing body temperature and without the proconvulsive effects of TRPV1 activation and thus may serve as a scaffold for the development of novel GABA(A) receptor modulators.