Data Entry: Please note that the research database will be replaced by UNIverse by the end of October 2023. Please enter your data into the system https://universe-intern.unibas.ch. Thanks
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 mu M (alpha(2)beta(2))-59.6 +/- 12.3 mu M (alpha(3)beta(2))). I-GABA modulation by piperine did not require the presence of a gamma(2S)-subunit, suggesting a binding site involving only alpha and beta subunits. I-GABA activation was slightly more efficacious on receptors formed from beta(2/3) subunits (maximal I-GABA stimulation through alpha(1)beta(3) receptors: 332 +/- 64% and alpha(1)beta(2): 271 +/- 36% vs. alpha(1)beta(1): 171 +/- 22%, p < 0.05) and alpha(3)-subunits (alpha(3)beta(2): 375 +/- 51% vs. alpha(5)beta(2):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. (C) 2013 The Authors. Published by Elsevier Inc. All rights reserved.
