Pyridine-Piperidine Alkaloids

Pyridine-Piperidine-Pyrolidine Alkaloids

• Reduction converts the tertiary base pyridine into the secondary base piperidine.
• These two nuclei form the basis for this group of alkaloids.
• This group is sometimes divided into three subgroups: derivatives of piperidine, derivatives of nicotinic acid, and derivatives of both pyridine and pyrolidine.
  • Example of piperidine derivative: lobeline from lobelia.
  • Example of nicotinic acid derivative: arecoline from areca.
  • Example of pyridine-pyrolidine derivative: nicotine from tobacco.

Biosynthesis of Pyridine-Piperidine Alkaloids

• Nicotine biosynthesis:
  • Tobacco plants incorporate ornithine into nicotine.
  • This incorporation leads to a symmetric labeling pattern in the nicotine molecule.
  • The N-methylpyrrolinium ion serves as a key intermediate that attaches to C-3 of the pyridine ring of nicotinic acid via electrophilic aromatic substitution.

Drugs Containing Pyridine-Piperidine Alkaloids

Tobacco

• Dried leaves of Nicotiana tabacum (Solanaceae).
• Cultivated for smoking.
• Contains 0.6-0.9% alkaloids.
• Nicotine:
  • An oily liquid alkaloid that turns yellow upon oxidation.
  • Acts as a ganglionic (nicotinic) cholinergic receptor agonist with complex pharmacological actions.
  • Chronic use may lead to psychological and physical dependence.
  • Causes peripheral vasoconstriction, atrial tachycardia, and increased blood pressure.
  • Is linked to heart disease and lung cancer in smokers where 50% of smokers die of heart disease and 20% die of lung cancer.
  • Carcinogenicity is likely due to N-nitroso nor nicotine rather than nicotine itself.
  • N-nitroso nor nicotine found in cigarettes, cigars, and chewing tobacco; even parts per billion concentrations pose health hazards.

Lobelia (Indian Tobacco)

• Dried leaves and tops of Lobelia inflata (Lobeliaceae/Campanulaceae).
• Contains 14 alkaloids, including piperidine and N-methylpiperidine derivatives, with lobeline as the major component.
• Lobeline:
  • Exists as colorless crystals, slightly soluble in water but soluble in hot alcohol.
  • Used for expectorant purposes.
  • Acts as a respiratory stimulant, but its effects are unreliable and brief.
  • Has effects similar to nicotine.
  • Used (0.5 to 1.5 mg doses of lobeline sulfate) in tablets or lozenges to aid in breaking tobacco habits and other drug addictions like amphetamines, cocaine, or alcohol.

Areca

• Dried, ripe seed of Areca catechu (Palmae).
• Contains reduced pyridine derivative alkaloids.
• Includes arecoline (arecaidine methyl ester), arecaidine (N-methyl guvacine), guvacine (tetrahydronicotinic acid), and guvacoline (guvacine methyl ester).
• Total alkaloid content is up to 0.45%.
• Uses:
  • Arecoline hydrobromide is used in veterinary medicine as an anthelmintic drug.
• Arecoline:
  • Parasympathomimetic (agonist) that acts on muscarinic receptors and, at high doses, on nicotinic receptors.
  • Causes vasodilation, hypotension, reflex tachycardia (low doses), stimulation of intestinal tone and peristalsis, increased secretions, miosis, and bladder contraction.

Pomegranate

• Pomegranate Root and Stem Bark or Granatum derived from Punica granatum (Punicaceae).
• Contains 0.5–0.9% volatile liquid alkaloids.
• Includes pelletierine and pseudopelletierine, along with approximately 22% tannin.
• Pelletierine tannate was used as an anthelmintic, specifically against tapeworms.

Conium (Poison Hemlock)

• Full-grown, unripe fruit of Conium maculatum (Umbellifereae).
• Contains alkaloids, including coniine and conhydrine.
• Used as an antispasmodic.
• Poisonous to humans and animals, potentially causing central nervous system depression, respiratory failure, acute rhabdomyolysis, acute renal failure, and death.
• Acts as a non-depolarizing blocker at the neuromuscular junction, similar to curare.

Piper

• Dried, full-grown, unripe fruit of Piper nigrum (Piperaceae).
• Contains 4.5-8% piperine.
• Primarily used as a condiment.
• Black pepper comes from unripe fruits, while white pepper comes from ripe fruits.
• Possesses irritant, stimulant, and febrifuge properties.
• Piperine structure: a piperidine moiety combined with piperic acid through an amide function.
• Hydrolysis of piperine yields piperidine, a liquid alkaloid.

Tropane Alkaloids

• Key alkaloids: (-)-hyoscyamine, atropine (racemate of hyoscyamine), and hyoscine (scopolamine).
• These compounds are esters, hydrolyzed by heating at 60°C with baryta water.
  • Atropine yields tropic acid and tropine upon hydrolysis.
  • Hyoscine yields tropic acid and oscine (formed via enzymatic hydrolysis, converted to oscine via chemical treatment).
• Extremely poisonous.
• Tropane:
  • A bicyclic amine with a pyrrolidine and a piperidine ring sharing a common nitrogen atom and two carbon atoms.
  • A dicyclic compound formed by condensation of a pyrrolidine precursor (ornithine) with three carbon atoms derived from acetate.
  • The 3-hydroxy derivative is known as tropine.
• Esterification of tropine with (-)-tropic acid yields hyoscyamine, which can be racemized to form atropine.

Biosynthesis of Tropane Alkaloids

• Hyoscyamine and Scopolamine:
  • Ornithine is stereospecifically incorporated to form the pyrrolidine ring of tropine.
  • The remaining three carbon atoms come from acetate, completing the piperidine moiety.
  • Methylation via transmethylation from a donor like methionine completes the tropine nucleus.
  • Esterification of tropic acid with tropine produces hyoscyamine.
  • Tropic acid is formed by intramolecular rearrangement of phenyllactate.
• Tropane Alkaloids Classification:
  • Solanaceous
  • Erythroxylon (Coca)

Solanaceous Tropane Alkaloids

• (-)-isomer is hyoscyamine, (+)-isomer not typically found in the plant.
• Atropine is the racemic form of hyoscyamine.
• Hyoscyamine is more active than atropine.
• Hyoscine (scopolamine) is an epoxide of atropine and exists as the (-)-isomer.
• Atrosine is the (±)-isomer of scopolamine.
• Over 200 tropane alkaloids have been recorded.

Drugs Containing Tropane Alkaloids

Belladonna (Deadly Nightshade Leaf)

• Dried leaf or root of Atropa belladonna (Solanaceae).
• Root has a higher alkaloid concentration (0.6%) than the leaves (0.4%).
• Alkaloids in the leaf: (-) hyoscyamine and traces of atropine (formed during extraction).
• Root contains apoatropine, belladonnine, and scopolamine.
• Uses:
  • Parasympathetic depressant and spasmolytic agent.
  • Anticholinergic properties used to control gastrointestinal tract motor activity and urinary tract spasms.
  • Decreases intestinal tone and paralyzes the ureters.
  • Reduces secretion flow (saliva, milk, sweat).
  • Induces passive mydriasis (pupil dilation).
  • Increases heart rate by suppressing vagal inhibition after a temporary bradycardia.
  • Causes vasodilation of cutaneous capillaries at toxic doses, especially on the face.

Hyoscyamus (Henbane)

• Dried leaves and flowering tops of Hyoscyamus niger (Solanaceae).
• Contains 0.04% total alkaloids (calculated as hyoscyamine), hyoscine, and traces of atropine.
• Used as a parasympatholytic agent, but the crude drug use in medicine is rare today.
• Egyptian Henbane (Hyoscyamus muticus):
  • Has a much higher alkaloid content (around 1.5%)
  • Consisting largely of hyoscyamine.
  • Cultivated in Egypt primarily for alkaloid extraction.

Stramonium (Datura stramonium)

• Dried leaves and flowering tops of Datura stramonium (Solanaceae).
• Contains up to 0.4% total alkaloids (calculated as hyoscyamine).
• Acts as an anticholinergic agent, similar to belladonna.
• Powdered Stramonium is used in preparations to be burned and inhaled for asthma relief.
• All of the above drugs are used as mydriatics, antispasmodics, parasympatholytics, and to decrease secretions (sweat, saliva, milk, etc.).
• Used as adjunctive therapy for peptic ulcers, functional digestive disorders, and diarrhea.

Cocaine Biosynthesis

• Feeding experiments with Erythroxylon coca have shown phenylalanine is incorporated into cocaine with radioactivity in the benzoyl group.
• The ecgonine moiety likely derives from ornithine and acetate.

Cocaine

• Habit-forming drug from the leaves of Erythroxylum coca (Erythroxylaceae).
• Coca leaves contain three types of alkaloids:
  • Ecgonine derivatives (cocaine, cinnamyl cocaine, α & β truxilline).
  • Tropine derivatives (tropacocaine, valerine).
  • Hygrine derivatives (hygroline, cuscohygrine).
• Ecgonine derivatives are the most commercially important, especially cocaine.
• Cocaine:
  • Methyl ester of benzoyl ecgonine.
  • Abused substance, inhaled or snorted, absorbed rapidly across pharyngeal mucosa.
  • Results in cerebral stimulation and euphoria.
  • Cocaine hydrochloride acts as a local anesthetic.
  • Applied topically to mucous membranes as a 2-5% solution.