Alkaloids

Why are alkaloids addictive?

Why are alkaloids addictive?

Because they can pass through BBB, especially in their free base form

classification of alkaloids

• chemical class

• taxonomic class

• biosynthetic class

• pharmacological class

Alkaloids are potent due to

nitrogen

Differentiate true and pseudoalkaloids

True alkaloids: nitrogen is incorporated to the core structure of its precursor molecules

pseudoalkaloids: nitrogen is acquired through transamination

1. nicotinic acid: pyridine

2. orn: pyrrolidine

piperidine but a pseudoalkaloid, acetated-derived

phenylalkylamine: from tyr

imidazole: from histidine

tropane: from orn

quinoline: from trp

quinolizidine: from lys

isoquinoline: from tyrosine

steroidal

purine

pyrrolizidine from orn

indole from trp

origin: L-ornithine

• polyamine

• pyrrolidine

• tropane

• pyrrolizidine

origin: L-lysine

• piperidine

• quinolizidine

• indolizidine

origin:: Nicotinic acid

pyridine

origin: L-tyrosine

• phenylalkylamine

• isoquinoline

• amaryllidaceae alkaloids

origin: L-tryptophan

• simple indole

• carboline

• terpenoid indole

• quinoline

• pyrroloindole

• ergot

origin:: Anthranilic acid

• quinazoline

• furoquinoline

• acridine

origin: L-histidine

imidazole

origin: by transamination (pseudoalkaloids)

• acetate-derived

• phenylalanine

• terpenoid

• steroidal

origin: purine

• xanthines

• saxitoxin

Found virtually in all living species. Regulators of cell growth, differentiation, and cell death. Examples are spermidine, spermine, and putrescine.

polyamines

polyamines that found in human semen

spermidine and spermine

from V. cholerae, rotting smell

putrescine

5-membered nitrogen-containing ring

pyrrolidine

tropane

tropane alkaloids that came from L-phe

hyoscyamine and cocaine

where are tropane alkaloids commonly isolated?

atropa sp. Datura sp., hyosyamus sp. Duboisia sp

T/F: Tropane alkaloids are toxic to humans but not to certain animals and has anticholinergic

True

Tropane alkaloids that have hypnotic, and hallucinogenic properties.

Hyoscyamine & hyoscine

Atropine

racemic hyoscyamine - medicinal

Atroscine

racemic hyoscine

(-) -hyoscine: medicinal

pyrrolizidine

Pyrrolizidine hepatotoxicity

Can only be converted into toxic form by the cytochrome enzymes → forms nucleophilic adducts

Organism produce the alkaloid N-oxide as but is converted back to free base by liver enzymes of those who consume the organism

examples are pelletierine, anaferine

piperidine

a piperidine alkaloid from Piperaceae that is a p-glycoprotein inhibitor (blocks this efflux protein to enhance bioavailability of the drugs)

piperine

From Fabaceae: Laburnum, Cystisus

Examples are Sparteine and lupanine

Smoking cessation: nicotinic AcH agonist

Herbivore deterrent

quinolizidine

from Fabaceae: Swainsona, astragalus, oxytropis

Antiviral

indolizidine

Name the two biosynthesis of nicotinic acid synthesis and give their precursors

• in microflora: from Trp

• in plants: Dihydroxy acetone P + iminoaspartic acid (from Asp)

pyridine alkaloid from Nicotiana tabacum (Solanaceae)

Oily, volatile alkaloid

Can be used for smoking cessation: nicotinic ACh agonist

nicotine

a phenylalkylamine alkaloid from Lophophora williamsii: peyote cactus

• 8-9% alkaloids in dried material

• psychedelic/hallucinogen (300-500 mg)

• Cultural significance in Aztecs/ Native Mexicans

mescaline

These can be found in succulents like cactus

co-occur with mescaline

Tetrahydroisoquinolines

opium alkaloids

• Air-dried latex (morphine is concentrated here) of Papaver somniferum

• Medicinal: India and China

• Black market: Afghanistan

BENZYLTETRAISOQUINOLINES

an opium alkaloid used as analgesic, narcotic

morphine

an opium alkaloid used for cough

codeine

an amaryllidaceae alkaloid from Galanthus sp., Narcissus sp., Leucojum sp.

Reversible AChE inhibitor

Enhances cognitive function in Alzheimer’s

galanthamine

simple indole

from Psilocybe sp.

• ~0.3% alkaloids

• Hallucinogenic (6-20 mg) - very potent hallucinogen

• Cultural significance in Aztecs and Native Mexicans

psilocybin, psilocin, baeocystin

From Peganum harmala (Zygophyllaceae) and Banisteriopsis caapi (Malpigiaceceae)

Serotonin antagonists

Hallucinogenic/psychoactive

Cultural significance in Aztecs and Native Mexicans

carboline

One of the major group of alkaloids in plants

best sources: Apocynaceae, Loganiaceace, and Rubiaceae

Main structural types:

• Corynanthe type

• Aspidosperma type

• Iboga type

terpenoid indole alkaloids

examples of terpenoid indole alkaloids

vinca alkaloids

T/F: Vinca alkaloids are dimeric

True

cinchona alkaloids

Cinchona sp (Rubiaceae)

• Bark: febrifuge

• Antimalarial (but its original use is for fever)

• Quinine: MDR malaria

• Quinidine: arrhythmia

quinoline

Physostigma venenosum (Fabaceae)

• Seeds: 1.5% alkaloids

  • Physostigmine is concentrated here

• Reversible anticholinesterase

• For glaucoma

pyrroloindole

a terpenoid indole alkaloid that is converted into ergotamine via non-iterative addition of amine (NRPS)

lysergic acid

quinazoline

From Peganum harmala (Zygophyllaceae), Adhatoda vasica (Acanthaceae)

Bronchodilator

peganine

furoquinolines

acridines

imadazole

T/F: The biosyntheis of dolichotheline, isolated from a cactus - Dolichothele sphaerica (catacaeae), is with experimental evidence

True

Jaborandi leaves

Pilocarpus sp. (Rutaceae)

Total alkaloids: 0.5–1.0%

glaucoma

cholinergic: muscarinic receptor agonist-causes constriction of the pupil and outflow of aqueous humor

pilocarpine

acetate derived pseudoalkaloid

from Poison hemlock, Conium maculatum (Apiaceae)

Muscular paralysis, convulsions

Total alkaloids (fruits): 1.6%

Major alkaloid: coniine, 90%

coniine

Ma Huang, Ephedra sp. (Ephedraceae)

Natural precursors for synthesis of amphetamines

Total alkaloids: 0.5-2.0%

CNS stimulant, sympatomimetic, acts on α- & β- adrenergic receptors (B3R -slimming)

Addictive, hallucinations, paranoia, psychosis

phenylalanine-derived pseudoalkaloids

terpenoid pseudoalkaloid

Gentiana lutea (Gentianaceae)

Mostly found as artefact formed when the plant is treated with NH3 that contains gentiopicroside

gentianine

• Solanum tuberosum (Solanaceae)

• Highest alk %: flowers, sprouts

• Lowest alk %: tubers

• Major: solasodine, alpha-chaconine

• poisonous, greenish coloration in tubers

• AChE & BuChE inhibitors

• Cell membrane disruptor, teratogenic, neurotoxic

steroidal alkaloids

steroidal alkaloids example

• solanidine (potato blight)

• tomatidine

xanthine purines

• Dinoflagellates (Alexandrium sp., Gymnodinium sp., Pyrodinium sp.) - red tide

• Freshwater cyanobacteria (Dolichospermum cicnale sp., Cyclindrospermopsis sp.)

• Na+ channel blocker

• Paralytic shellfish poisoning

saxitoxin

• Found in internal organs or skin of puffer fish, Tetraodon lineatus (Tetraodontidae), porcupine fish, octopus, cuttlefish, starfish

• Bacteria: Actinomyces, Bacillus, Pseudomonas, Vibrio

• Inhibits voltage-gated Na+-channel

• Diaphragm paralysis, respiratory failure

tetrodotoxin