Yangonin, a kavalactone from Piper methysticum, is a novel CB1 receptor ligand

Transcription

1 Yangonin, a kavalactone from Piper methysticum, is a novel B1 receptor ligand István Ujváry 1, Alessia Ligresti 2, Rosaria Villano 2, Marco Allarà 2 and Vincenzo Di Marzo 2 1 ikem BT, Budapest, Hungary 2 Endocannabinoid Research Group, Institute of Biomolecular hemistry, onsiglio Nazionale delle Ricerche, Pozzuoli, Italy 22 nd Annual Symposium of the International annabinoid Research Society July 22 27, 2012, Freiburg, Germany

2 Structural diversity of selected phytocannabinoids H 2 N H Echinacea isobutylamide B 2 receptor agonist Raduner et al, 2006 H falcarinol B 2 receptor antagonist Leonti et al, 2010 H 2 b-caryophyllene B 1 receptor agonist Gertsch et al, 2008 H H H H H H H N H diindolylmethane B 2 receptor agonist Yin et al, 2009 P H desulfohaplosamate (from sponge) B 2 receptor ligand hianese et al, 2011 N H Ac H 2 rutamarin B 2 receptor ligand Rollinger et al, 2009 N H N 2 3,6-oxidovoacangine B 2 receptor antagonist Kitajima et al, H H oleamide FAAH inhibitor Maurelli et al, 2005 NH 2 H kaempferol FAAH inhibitor Thors et al, 2008 H H pristimerin MAGL inhibitor King et al, 2009

3 The kava plant (Piper methysticum Forster; Piperaceae) 21 November 2011, Vanuatu

4 The kava drink (kawa, kava-kava, yaquna) and preparations from it awa bitter; meθusmέnos - inebriating drink John LaFarge (1891) Lebot V, Merlin M & Lindstrom L (1992) Kava The Pacific Elixir

5 Allgemeine Wirkungen des Kawagetränkes...Wirkung wie die einer starken Dose eines spirituösen Getränkes oder vielmehr eine Betäubung, wie sie pium hervorruft, beobachtet wurde. Auch mit der Wirkung des Lattichs und der des Haschisch ist die Kawawirkung verglichen worden.

6 Main effects mood enhancer anxiolytic sedative sleep inducer local anesthetic analgetic anticonvulsant Pharmacology of kava ther physiological effects observed after drinking kava: paresthesia (face, extremities), body sway, ataxia, muscle relaxation, hypothermia, slightly bloodshot eyes ognitive processes only slightly affected. Preparations form various parts of the plant are used in traditional medicine For some commercial kavalactone extracts hepatotoxicity of unknown etiology has been reported leading to the restriction / ban of sales of such extracts in several countries in Europe (since 2002).

7 The main kavalactones (a-kavapyrones) ( ) +12 minor kavalactones (~5%) kavain 7,8-dihydrokavain yangonin desmethoxyyangonin methysticin 7,8-dihydromethysticin

8 Reported pharmacological targets of kavalactones GABAA receptor, NE uptake, DA uptake, 5-HT level, kavain PGE2 / TXA2 formation inhibition, X inhibition, voltage-gated Na+ channels 7,8-dihydrokavain GABAA receptor, DA uptake, 5-HT level, voltage-gated Na+ channels, X inhibition, MA-B inhibition yangonin GABAA receptor, DA level, X inhibition, MA-B inhibition desmethoxyyangonin GABAA receptor, DA level, 5-HT level, X inhibition, MA-B inhibition methysticin GABAA receptor, NE uptake, X inhibition, MA-B inhibition 7,8-dihydromethysticin GABAA receptor, 5-HT level, voltage-gated Na+ channels, X inhibition, MA-B inhibition kavalactone-rich extract GABAA receptor, DA level, D2 receptor, opioid receptors, 5-HT7 receptors haracter size indicates level of activity: < 1 mm; mm; mm; low but measurable effect

9 Binding of kavalactones to human recombinant B 1 receptors in vitro displacement of [ 3 H]P 55,940 binding (mean values, n = 3) compound K i mm Displacement at 10 mm (%) 7,8-dihydrokavain > (±)-kavain > ,8-dihydromethysticin > methysticin > yangonin 0.72 ± (98.4% at 25 mm) D 9 -TH not tested For experimental details, see: Ligresti A et al (2012) Pharmacol Res, 66, 163

10 Binding of kavalactones to human recombinant B 2 receptors in vitro displacement of [ 3 H]P 55,940 binding (mean values, n = 3) compound K i mm Displacement at 10 mm (%) 7,8-dihydrokavain > (±)-kavain > ,8-dihydromethysticin > methysticin > yangonin > D 9 -TH not tested For experimental details, see: Ligresti A et al (2012) Pharmacol Res, 66, 163

11 Displacement curves of TH and yangonin binding to B receptors each symbol represents the mean per cent displacement ± SEM (n = 3) % displacement of [ 3 H]P 55,940 binding D 9 -TH (B 1 ) D 9 -TH (B 2 ) yangonin (B 1 ) yangonin (B 2 ) concentration, log M

12 Binding of selected new synthetic kavalactone analogues to hb 1 and hb 2 receptors compound % displacement at 10 mm* B 1 B H *K i values for both receptors are >10 mm for all analogues

13 Effect of kavalactones on endocannabinoid catabolism Background Glutathione has been implicated in the metabolism of kavalactones kavain Interaction with Ser / ys residues at / near active site? FAAH inhibition (rat brain enzyme preparation using AEA as substrate) I 50 > 10 mm for all natural and synthetic compounds ( % inhibition at 10 mm) MAGL inhibition (cytosolic S enzyme preparation using 2-AG as substrate) I 50 > 10 mm for all natural and synthetic compounds ( % inhibition at 10 mm) For experimental details, see: Ligresti A et al (2012) Pharmacol Res, 66, 163

14 Summary yangonin is a B 1 receptor ligand kavalactones may contribute to the complex pharmacology of kava drink & kava preparations kavalactones are novel phytocannabinoid chemotypes structure optimization of synthetic analogues might lead to more active receptor ligands H