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

Abstract

Graphical abstract

A pharmacological basis of herbal medicines for epilepsy

“…Methysticine from Piper methysticum (kava) was shown to inhibit Na + channels in CA1 hippocampal neurons [164]. The alkaloid piperine has been shown to both inhibit GABA A receptors and activate transient receptor potential vanilloid 1 (TRPV1) receptors [165,166]. Eugenol was found to activate transient receptor potential ankyrin 1 (TRPA1) channels, though at a high EC 50 of 261.5 μM [167], but inhibit the TRPL channels [168].…”

Natural Products as Potential Human Ether-A-Go-Go-Related Gene Channel Inhibitors – Screening of Plant-Derived Alkaloids

“…I hERG inhibition (%) at 100 µM (−)-Argemonine (1) 10.0 ± 0.8 (−)-Eschscholtzine (2) 14.6 ± 2.0 (−)-Neocaryachine (3) 9.8 ± 0.4 (−)-Californidine (4) 0.0 ± 0.0 (+)-Reticuline (5) 28.1 ± 2.0 Papaverine (6) 33.6 ± 3.4 (−)-Ephedrine (7) 0.0 ± 0.0 Indirubin (8) 0.0 ± 0.0 (−)-Sparteine (9) 0.0 ± 0.0 Harmine (10) 27.5 ± 3.1 Vasicine (11) 2.2 ± 0.3 Vasicinone (12) 0.0 ± 0.0 Tryptanthrin (13) 0.0 ± 0.0 8-Oxoberberine (14) 3.7 ± 1.9 8-Oxocoptisine (15) 0.9 ± 0.9 Protopine (16) 88.4 ± 1.9 (−)-Remerine (17) 42.7 ± 7.3 (+)-Bulbocapnine (18) 72.0 ± 1.6 (+)-N-methyllaurotetanine (19) 81.4 ± 2.9 (+)-Boldine (20) 65.8 ± 5.3 Sanguinarine (21) 34.8 ± 12.1 Dihydrosanguinarine (22) 22.5 ± 4.3 (+)-Chelidonine (23) 56.8 ± 8.2 (+)-Corynoline (24) 72.6 ± 2.4 (+)-Haemanthamine (25) 0.0 ± 0.0 (+)-Hippeastidine (26) 28.2 ± 1.1 (−)-Galanthine (27) 1.3 ± 0.3 Noscapine (28) 6.8 ± 3.0 Emetine (29) 3.3 ± 1. …”

“…Moderate hERG inhibitory activity was observed for the TCM herbal drug Huanglian (rhizomes of Coptis chinensis Franch., Ranunculaceae) and black pepper fruits (Piper nigrum L., Piperaceae), and successfully tracked to dihydroberberine and piperine, respectively [10,11]. Given the importance of both alkaloids, in particular of piperine as a major constituent in pepper fruits and as a starting point for the development of promising GABA A receptor modulators [12], we complemented our in vitro screening for hERG blockers with the evaluation of a focused alkaloid library. Compounds were selected to include structurally diverse and pharmacologically important alkaloid scaffolds, and compounds with known and relevant pharmacological activities, such as tryptanthrin, emetine, yohimbine, reserpine, and galanthamine.…”

Nitrogenated honokiol derivatives allosterically modulate GABAA receptors and act as strong partial agonists

“…6,9 To elicit I GABA , the chamber was perfused with 120 lL of GABA-or compound-containing solutions, respectively, at a volume rate of 300 lL/s. 11 Care was taken to account for possible slow recovery from increasing levels of desensitization in the presence of high drug concentrations. The duration of washout periods was therefore extended from 1.5 min (<10 lM compounds) to 30 min (P10 lM compounds), respectively.…”