Picrotoxinin

Neurosci Lett . 1994 Apr 25;171(1-2):67-9.

Blocking actions of picrotoxinin analogues on insect (Periplaneta americana) GABA receptors[Pubmed: 7916140]

Five Picrotoxinin analogues were examined on GABA-gated chloride channels of an identifiable cockroach (Periplaneta americana) motor neurone (Df). Substitution of the bridgehead hydroxyl at the C-6 position of the Picrotoxinin molecule by a fluorine atom (fluoroPicrotoxinin) had little effect, whereas acetylation of the same functional group (Picrotoxinin acetate) substantially reduced the effectiveness of the parent compound. Conversion of the terminal isopropenyl group to an acetyl (alpha-picrotoxinone) or hydration of the double bond (picrotin) also reduced activity. Dendrobine, a naturally-occurring Picrotoxinin-like compound had very little effect on GABA-induced responses at concentrations up to 1.0 x 10(-5) M. The present results suggest that the size and the ability of the bridgehead hydroxyl to undergo hydrogen bond formation and the lipophilic nature of the terminal isopropenyl group profoundly affect the inhibitory actions of the Picrotoxinin molecule on insect neuronal GABA-gated chloride channels.

Proceedings of the Royal Society B Biological Sciences, 1986, 227(1247):191-216.

Studies on the mechanism of action of picrotoxinin and other convulsants at the crustacean muscle GABA receptor.[Reference: WebLink]

The actions of Picrotoxinin, bicuculline and penicillin-G were investigated on the GABA-receptor system of lobster muscle by using intracellular recording. The highly potent antagonist, Picrotoxinin, produced a lateral shift and depression in the maximum of the GABA dose--conductance curve (designated as mixed antagonism); bicuculline, a weak antagonist, caused only a depression in the maximum with little or no lateral shift, whereas penicillin-G, an even weaker antagonist, produced a greater depression at the top of the dose--response curve.
METHODS AND RESULTS:
The possible sites of antagonist action were examined, with a critical re-evaluation of a drug-receptor model previously proposed to account for the antagonistic behaviour of Picrotoxinin (the mixed antagonistic model); this model was extended to include the actions of bicuculline and penicillin-G. Antagonism was examined (i) towards different GABA receptor agonists; (ii) in various external anion media; (iii) at varying external pH; and (iv) when two different antagonists were combined. The GABA agonists were differentially antagonized by Picrotoxinin and bicuculline, but external pH and substituent anions caused only minor perturbations to the inhibition. Combination experiments suggested at least three sites for GABA antagonists binding on crustacean muscle: (i) the GABA recognition site or sites; (ii) the ionic selectivity site in the ionophore; and (iii) a highly lipophilic site which may be part of the GABA receptor or ionophore. The mixed antagonism model accounted for the pH and external anion data but required modification to a cyclic scheme to explain the antagonism of a partial agonist. A model based on two-state receptor theory could only account for the antagonism of GABA if Picrotoxinin was assumed not only to perturb L (the R rightleftharpoons T conformation constant) but also to affect the agonist binding affinity.
CONCLUSIONS:
It is suggested that Picrotoxinin and bicuculline may antagonize GABA responses by stabilizing the closed form of the activated channel, whereas penicillin-G may block the channel in the open state.

Biochem Pharmacol . 1993 May 5;45(9):1783-9.

Picrotoxin as a potent inducer of rat hepatic cytochrome P450, CYP2B1 and CYP2B2[Pubmed: 8494537]

The induction by the central stimulant picrotoxin of hepatic drug-metabolizing enzymes was studied in rats. The hepatic content of P450 and the activity of benzphetamine N-demethylation increased gradually after administration of picrotoxin dissolved in drinking water (2 mg/mL), to three-times higher levels than the initial values at the third day of treatment. The increase in benzphetamine N-demethylase activity by picrotoxin was somewhat higher than the increase produced by phenobarbital. Supporting these results, immunoblot analysis showed that CYP2B1 and 2B2 proteins in the liver microsomes were increased by picrotoxin Picrotoxinin and picrotin, which are components of the picrotoxin molecule, had the same ability to induce the hepatic activity of benzphetamine N-demethylation. The liver microsomal activities of testosterone 16 alpha- and 16 beta-hydroxylation were enhanced significantly after treatment with Picrotoxinin and picrotin. However, benzo[a]pyrene 3-hydroxylation, aniline 4-hydroxylation, and testosterone hydroxylations at the 2 alpha- and 7 alpha-positions were not increased by Picrotoxinin and picrotin treatment. In addition to monooxygenase, significant induction of glutathione S-transferase activity for 1-chloro-2,4-dinitrobenzene and UDP-glucuronyltransferase activity for 4-hydroxybiphenyl and 4-nitrophenol was also observed by pretreatment of picrotoxin. These results clearly indicate that picrotoxin is an inducer of phenobarbital-inducible liver enzymes.