Novel multifunctional pharmacology of lobinaline, the major alkaloid from Lobelia cardinalis

Abstract

In screening a library of plant extracts from ~1000 species native to the Southeastern United States, Lobelia cardinalis was identified as containing nicotinic acetylcholine receptor (nicAchR) binding activity which was relatively non-selective for the α4β2- and α7-nicAchR subtypes. This nicAchR binding profile is atypical for plant-derived nicAchR ligands, the majority of which are highly selective for α4β2-nicAchRs. Its potential therapeutic relevance is noteworthy since agonism of α4β2- and α7-nicAchRs is associated with anti-inflammatory and neuroprotective properties. Bioassay-guided fractionation of L. cardinalis extracts led to the identification of lobinaline, a complex binitrogenous alkaloid, as the main source of the unique nicAchR binding profile. Purified lobinaline was a potent free radical scavenger, displayed similar binding affinity at α4β2- and α7-nicAchRs, exhibited agonist activity at nicAchRs in SH-SY5Y cells, and inhibited [3H]-dopamine (DA) uptake in rat striatal synaptosomes. Lobinaline significantly increased fractional [3H] release from superfused rat striatal slices preloaded with [3H]-DA, an effect that was inhibited by the non-selective nicAchR antagonist mecamylamine. In vivo electrochemical studies in urethane-anesthetized rats demonstrated that lobinaline locally applied in the striatum significantly prolonged clearance of exogenous DA by the dopamine transporter (DAT). In contrast, lobeline, the most thoroughly investigated Lobelia alkaloid, is an α4β2-nicAchR antagonist, a poor free radical scavenger, and is a less potent DAT inhibitor. These previously unreported multifunctional effects of lobi-naline make it of interest as a lead to develop therapeutics for neuropathological disorders that involve free radical generation, cholinergic, and dopaminergic neurotransmission. These include neurodegenerative conditions, such as Parkinson’s disease, and drug abuse.

Microfluidic capillary zone electrophoresis mass spectrometry analysis of alkaloids in Lobelia cardinalis transgenic and mutant plant cell cultures

“…Lastly, the lobeline‐like molecules, peaks 5–11 (see Table and Supporting Information ), also displayed a generally increasing trend. Though lobeline (8,10‐diphenyllobelionol‐C 22 H 27 NO 2 ) itself was not observed in these samples and has not been found in extracts of intact plant material of L. cardinalis in the past, both lobinaline and lobeline derive from similar precursors . Molecules very similar to these have been reported in the literature to have activity both on the DAT and on nicotinic acetylcholine receptors .…”

“…This master peak list was then used to select several known or putatively identified molecules of interest for a statistical comparison list. Lobinaline and lobinaline‐like derivatives, henceforth referred to as “lobinalines” were initially set as top priority molecules due to the hDAT inhibitory activity of lobinaline reported previously . Lobinalines all share a common capability to become doubly charged molecules during electrospray ionization experiments.…”

“…The alkaloids in question for this application of the microfluidic device are those found in the cardinal flower, Lobelia cardinalis . L. cardinalis produces a binitrogenous alkaloid, lobinaline (decahydro‐1‐methyl‐5,7‐diphenyl‐6‐(3,4,5,6‐tetrahydro‐2‐pyridinyl)‐quinoline‐C 27 H 34 N 2 – Supporting Information ), recently shown to have inhibitory activity on the dopamine transporter (DAT) . In order to find novel metabolites with similar activity, Naprogenix (Lexington, KY) successfully transformed L. cardinalis to produce hairy root cultures expressing the human dopamine transporter (hDAT).…”

Investigation of the Mechanisms of Neuroprotection Mediated by Lobelia Species via Computational Network Pharmacology and Molecular Modeling

“…Certain species of Lobelia, such as Lobelia in ata and Lobelia cardinalis are extensively characterized and the pharmacological properties of their chemical constituents are well-studied (60). Among them, the pyridine alkaloids lobeline and lobinaline were thoroughly investigated (27,(61)(62)(63).…”

Target-directed discovery and production of pharmaceuticals in transgenic mutant plant cells

“…Target proteins have previously been expressed in plant cells as screens (Littleton 2007, Doukhanina et al 2007, Zhao et al 2012, Gunjan et al 2013), but this is the first report in which survival of mutant plant cells expressing a foreign target protein has been used to direct secondary metabolism toward a specific pharmacological phenotype. Proof of concept uses Lobelia cardinalis , which contains lobinaline, a novel inhibitor of the human dopamine transporter (DAT) (Littleton et al 2004, Brown et al 2016). Metabolites with this activity have evolved in plants to inhibit similar transporter proteins in the brains of herbivorous insects to deter feeding (Chen et al 2006)).…”