Falcarindiol Allosterically Modulates GABAergic Currents in Cultured Rat Hippocampal Neurons

Abstract

Falcarindiol (1), a C-17 polyacetylenic diol, shows a pleiotropic profile of bioactivity, but the mechanism(s) underlying its actions are largely unknown. Large amounts of 1 co-occur in water hemlock (Oenanthe crocata) along with the convulsant polyacetylenic toxin oenanthotoxin (2), a potent GABA(A) receptor (GABA(A)R) inhibitor. Since these compounds are structurally and biogenetically related, it was considered of interest to evaluate whether 1 could affect GABAergic activity, and for this purpose a model of hippocampal cultured neurons was used. Compound 1 significantly increased the amplitude of miniature inhibitory postsynaptic currents, accelerated their onset, and prolonged the decay kinetics. This compound enhanced also the amplitude of currents elicited by 3 μM GABA and accelerated their fading, reducing, however, currents evoked by a saturating (10 mM) GABA concentration. Moreover, kinetic analysis of responses to 10 mM GABA revealed that 1 upregulated the rate and extent of desensitization and slowed the current onset and deactivation. Taken together, these data show that 1 exerts a potent modulatory action on GABA(A)Rs, possibly by modulating agonist binding and desensitization, overall potentially decreasing the toxicity of co-occurring GABA-inhibiting convulsant toxins.

Comprehensive Analysis of Mouse Bitter Taste Receptors Reveals Different Molecular Receptive Ranges for Orthologous Receptors in Mice and Humans

“…Homoserine lactones were acquired from Darren Furniss (University of Nottingham, United Kingdom). Noncommercial bitter terpenoids were obtained by isolation from their plant sources (107)(108)(109)(110)(111)(112). All other substances were available from previous studies (32,37).…”

Dietary Acetylenic Oxylipin Falcarinol Differentially Modulates GABAA Receptors

“…For the α 1 β 2 γ 2L receptors, which play a crucial role in phasic inhibition and in being also the most abundant GABA A R in the CNS, low falcarinol (1a) concentrations enhanced current amplitude elicited by nonsaturating GABA, similar to previous observation for falcarindiol (1a) in primary hippocampal neurons. 16 This effect may suggest an upregulation of agonist binding rate, but such a mechanism would predict also acceleration of the current onset that has not been observed in the present experiments. Most likely, 1a may affect not only binding, but also gating (e.g., the opening/closing rate), although this possibility would require a detailed receptor kinetic study beyond the scope of this current investigation.…”

“…Higher concentrations of 1b (1 μM) significantly enhanced the current responses, but the effect was still weaker than that observed for 1a at the same concentrations. 16 In addition, the impact of 1a on the time course of GABA-evoked currents (except for fading) was larger than in the case of 1b. Substantial changes in the modulatory actions of 1a and 1b on GABA A Rs exist, underscoring the specificity of their interactions with these receptors.…”

“…13,14 Minor structural changes greatly modify the modulatory effects on GABA A Rs, with allosteric effects and open channel block being strongly dependent on polarity, 15 as shown by the observation that the related polyacetylene falcarindiol (1b) enhances rather than inhibits current responses to low GABA concentrations (Scheme 1). 16 Falcarindiol (1b) and falcarinol (1a) react in the same way with thiols, 8,11 but show different biological profiles, since falcarindiol is completely inactive in assays of CB1 binding 7 and also displays lower cytotoxic activity than falcarinol. 17 These differences highlight the role of the molecular milieu for covalent ligands 18 and provide a rationale for investigating the action of falcarinol on GABA A receptors.…”

Total Synthesis of Chiral Falcarindiol Analogues Using BINOL-Promoted Alkyne Addition to Aldehydes

“…The unique diynol structure and the configuration of the chiral centers are believed to be closely associated with their biological functions [4]. For example, (3R,8S)-falcarindiol, which has a typical diynol moiety, has shown great anticancer activity and neuron-protective effect at low concentrations [5][6][7][8]. However, the low content of falcarindiol analogues in natural resources limits their further study and application [9].…”