Lobeline. ! Molecular Formula C 22 H 27 NO 2. ! Alkaloid from Lysine. ! Lobeline is the main Alkaloid present in the plant Lobelia inflata CH 3

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Allyson Davis
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1 Lobeline C 3! Molecular Formula C ! Alkaloid from Lysine! Lobeline is the main Alkaloid present in the plant Lobelia inflata

2 Discovery! Lobelia inflata was named after Matthias de Lobel ( ) who was a famous French botanist. ther common names for the plant are: Indian Tobacco, vomitwort, gagroot, asthma weed and eyebright! The structural identification of Lobeline was reported by Wieland in 1925! istorically, L. inflata was prepared in compressed oblong packages by the shakers of ew Lebanon for importation to England.! Chewing the plant produces effects like that of nicotine, such as sensation to the tongue and stomach, as well as CS effects. owever there is no obvious structural resemblance to nicotine apparent C 3 S-(-)-icotine

3 Biological Activity! The earliest known use of lobeline was as a safe, short-acting respiratory stimulant! The powerful respiratory stimulant action of Lobeline has been advantageous for stimulation of respiration in bronchitic asthma, whooping cough, and pneumonia! Lobeline is a primary stimulant and secondary depressant of sympathetic and parasympathetic ganglia, the adrenal medulla, the neuromuscular junction, and chemoreceptors.! Lobeline may have some clinical benefit as a smoking cessation agent, but remains controversial

4 Mode f Action! The Classical mechanism of action had been categorized as a nicotinic receptor agonist at the nicotinic acetylcholine receptor (nachr), but more recent studies suggest it to be an antagonist! A disconnect appears between the ability of lobeline to bind to nachrs and its effects in functional assays probing these nachr subtypes! Using studies with rats, researchers have found that lobeline does not release either dopamine or dihydroxyphenylacetic acid (DPAC) in vivo! Research has recently discovered that lobeline inhibits nicotine-evoked [ 3 ]dopamine overflow in rat striatial slices! The primary mechanism of action of lobeline is to inhibit dopamine uptake and promote dopamine release from synaptic vesicles within dopaminergic terminals, perturbing fundamental storage and release mechanisms! So, the previously Classical mechanism of action of lobeline as a nicotinic receptor agonist is clearly not consistent with its more recently reported neuropharmacological properties

5 ! This shows the proposed mechanism of action of lobeline to inhibit dopamine uptake into synaptic vesicles! This results in a corresponding redistribution of presynaptic dopamine storage and an increase in the cytosolic dopamine pool! This increase in cytosolic dopamine leads to an increase in DPAC as a result of metabolism of the cytosolic dopamine pool by monoamine oxidase! This redistribution leads to a decrease in the cytosolic dopamine pool available for reverse transport by the dopamine transporter (DAT)

6 Biosynthesis verview Lysine Piperidinium Cation + Lobeline 2 benzoylacetyl-coa enolate anions Cinnamic Acid Phenylalanine

7 Piperidinium Cation Formation -C 2 PLP oxidative deamination via diamine oxidase Cadaverine Schiff base formation + + Piperideine Piperidinium Cation

8 Additions of 2 benzoylacetyl-coa Mannich reaction, hydrolysis and decarboxylation + _ CSAoC oxidation + Piperidinium Cation benzoylacetyl-coa enolate anion Mannich reaction, hydrolysis and decarboxylation benzoylacetyl-coa Cinnamic Acid SAM 2 Phenylalanine C 3 Reduction ADP Lobelanine C 3 Lobeline

9 Future Directions of Lobeline! Recent studies of Lobeline have found that lobeline reduces the cytosolic pool of dopamine and therefore diminishing methamphetamine evoked dopamine release! Due to this mode of action there are current studies developing drug therapies for methamphetamine abuse! Analogs of lobeline are also being studied to determine if the whole compound is necessary for its mode of action! These analogs have been shown to have a decrease in activity of more than 200 to 300 times

I. OVERVIEW DIRECT. Drugs affecting the autonomic nervous system (ANS) are divided into two groups according to the type of

I. OVERVIEW DIRECT. Drugs affecting the autonomic nervous system (ANS) are divided into two groups according to the type of THE CHOLINERGIC NEURON 1 I. OVERVIEW DIRECT Drugs affecting the autonomic nervous system (ANS) are divided into two groups according to the type of ACTING neuron involved in their mechanism of action.