Alkaloids: Properties, Occurrence and Naming

Alkaloids Overview

• Alkaloids are organic nitrogenous compounds that are chemically, biochemically, and physiologically diverse.
• They are mostly basic due to an amino nitrogen, and many exhibit significant physiologic activity.
• Alkaloids are primarily sourced from plants, but can also be found in animals, fungi, and bacteria, and can be reproduced synthetically in labs.

Occurrence in Plants

• Alkaloids can be located in various parts of plants, including seeds, fruits, leaves, underground stems, roots, rhizomes, and barks.
• Examples: Nux vomica and areca in seeds; black pepper and conium in fruits; belladonna and hyoscyamus in leaves; aconite and belladonna in roots; ipecac and hydrastis in rhizomes and roots; cinchona and pomegranate in barks; ergot in fungi.

Naming Conventions

• Alkaloid names derive from various sources: the genus of the plant, the species of the plant, the common name of the drug, their physiologic activity, or their discoverer.
• Chemical rules dictate that alkaloid names end in "ine".

Toxicity and Function

• Alkaloid intoxication in animals is often due to accidental ingestion of contaminated food with alkaloid-containing plants.
• The amount of alkaloid ingested and the animal's sensitivity are crucial factors in intoxication.
• Some alkaloids, like cyclopamine in Veratrum californicum, can cause teratogenic effects in mammals.
• The possible functions of alkaloids in plants are poisonous agents, end products of detoxification, regulatory growth factors, and reserve substances.

Pharmacologic Action

• Alkaloids have varied pharmacologic actions: some are analgesics and narcotics (morphine, codeine), while others are central stimulants (strychnine, brucine).
• Some act as mydriatics (atropine, homatropine), while others are myotics (physostigmine, pilocarpine).
• They can also affect blood pressure, with some causing a rise (ephedrine) and others a fall (reserpine).

Properties

• Most alkaloids are crystalline substances that form salts with acids.
• In plants, they exist in the free state, as salts, or as N-oxides.
• Alkaloids contain carbon, hydrogen, and nitrogen, with most also containing oxygen. Some, like coniine, nicotine, and sparteine, are liquids lacking oxygen.
• Colored alkaloids are rare, but examples include yellow berberine and copper-red sanguinarine salts.
• Most alkaloids contain one nitrogen atom, with exceptions like ergotamine having up to five.
• Alkaloids can be primary, secondary, or tertiary amines, behaving as bases with varying degrees of basicity.
• They form salts with aqueous mineral acids, and free amines are liberated when alkaloid salts are treated with hydroxide ions.

Quaternary Ammonium Compounds

• Quaternary ammonium compounds have four organic groups covalently bonded to nitrogen.
• Their positive charge is balanced by a negative ion.
• They are unaffected by hydroxide ions and have different chemical properties from amines.

Solubility

• Alkaloids are generally insoluble or sparingly soluble in water, but their salts are freely soluble.
• Free alkaloids are soluble in nonpolar solvents like ether or chloroform, while their salts are insoluble in these solvents.

Tests for Alkaloids

• Alkaloids precipitate from neutral or slightly acidic solutions using reagents such as Mayer's reagent, Wagner's reagent, tannic acid, Hager's reagent, and Dragendorff's reagent.
• Precipitates can be amorphous or crystalline with various colors, but caution is needed as proteins also give precipitates with these reagents.
• Caffeine and other purine derivatives do not precipitate like most alkaloids but are detected using the murexide test.

Biosynthesis

• The biosynthesis of many alkaloid structures can be rationalized through chemical reactions involving amino acids.
• Key reactions include decarboxylation and transamination of amino acids.
• The major amino acids involved in biosynthesis are lysine, ornithine, phenylalanine, tyrosine, and tryptophan.

Classification

• Alkaloids are classified based on the nature of the basic chemical structures from which they derive.
• Arecoline, pelletierine, lobeline, coniine, and nicotine are derivatives of pyridine and piperidine.
• Atropine, hyoscyamine, and hyoscine are derivatives of tropane, a condensation product of pyrrolidine and piperidine.

Extraction

• Fractional extraction is used to separate alkaloids, starting from less polar to more polar solvents.
• Defatting is done using non-polar solvents to remove chlorophyll, wax, volatile oils, and fixed oils.
• Filtration, use methanol or ethanol 95% for marc, evaporate by rotary evaporator for concentrating.
• Add tartaric acid 2% and ethyl acetate to separate into organic and aqueous layers.
• Organic layer contains weak or neutral alkaloids. Aqueous layer (acidic) contains alkaloidal salt. Add NH3 to break the salt.

Purification

• Direct crystallization is a simple procedure but rarely succeeds with crude mixtures.
• Distribution between immiscible solvents involves using a dilute acid solution, then recovering alkaloids with ammonium hydroxide and a water-immiscible organic solvent.

Pyridine-Piperidine-Pyrolidine Alkaloids

• Pyridine converts to piperidine upon reduction.
• Examples include lobeline from lobelia (piperidine derivatives), arecoline from areca (nicotinic acid derivatives), and nicotine from tobacco (pyridine-pyrolidine derivatives).
• Nicotine's biosynthetic pathway involves ornithine and the N-methylpyrrolinium ion.

Drugs Containing Pyridine-Piperidine Alkaloids

• Tobacco: Dried leaves of Nicotiana tobacco containing 0.6-0.9% alkaloids, mainly nicotine, an oily liquid alkaloid.
• Nicotine acts as a ganglionic cholinergic receptor agonist with effects on autonomic ganglia, adrenal medulla, neuromuscular junction, and the brain. -Chronic use leads to psychological and physical dependence. Nicotine affects the cardiovascular system, causing vasoconstriction, tachycardia, and increased blood pressure. -Carcinogenicity may be due to N-nitroso nor nicotine.
• Lobelia (Indian Tobacco): Dried leaves and tops of Lobelia inflate containing 14 alkaloids, including lobeline, lobelanine, and lobelanidine. -Lobeline is a respiratory stimulant with effects resembling nicotine. -Used in tablets to aid in breaking tobacco habits and treating other drug addictions.
• Areca: Dried ripe seed of Areca catechu containing pyridine derivatives like arecoline, arecaidine, guvacine, and guvacoline. -Arecoline Hydrobromide is used as an anthelmintic in veterinary medicine. -Arecoline acts as a parasympathomimetic on muscarinic and nicotinic receptors, causing vasodilation, hypotension, tachycardia, increased intestinal tone, secretions, myosis, and bladder contraction.
• Pomegranate: Root and stem bark of Punica granatum containing volatile liquid alkaloids, mainly pelletierine and pseudopelletierine. -Pelletierine tannate was formerly used as an anthelmintic, specifically against tapeworms.
• Conium (Poison Hemlock): Unripe fruit of Conium maculatum containing coniine and conhydrine. -Used as an antispasmodic. Poisonous effects include central nervous system depression, respiratory failure, and neuromuscular blockade.
• Piper: Dried unripe fruit of Piper nigrum containing 4.5-8% piperine. -Used as a condiment with irritant, stimulant, and febrifuge activity. Hydrolysis yields piperidine.

Tropane Alkaloids

• Principal alkaloids include (−)-hyoscyamine, atropine, and hyoscine (scopolamine).
• These compounds are esters hydrolyzed to tropic acid and either tropine or oscine.
• They are extremely poisonous.
• Tropane is a bicyclic amine with pyrrolidine and piperidine rings sharing common atoms.
• The 3-hydroxy derivative of tropane is tropine.

Biosynthesis of Tropane Alkaloids

• Hyoscyamine and scopolamine derive from ornithine, acetate, and methionine.
• Tropic acid is formed by an intramolecular rearrangement of phenyllactate.
• Tropane alkaloids are classified into solanaceous tropane alkaloids and erythroxylon (coca) alkaloids.

Solanaceous Tropane Alkaloids

• (−)-Hyoscyamine is the active isomer; atropine is its racemate.
• Hyoscine (scopolamine) is an epoxide of atropine.
• Numerous tropane alkaloids have been recorded, with semi-synthetic derivatives of medicinal importance.

Drugs Containing Tropane Alkaloids

• Belladonna (Deadly Night Shade Leaf): Dried leaf or root of Atropa belladonna. -The root is richer in alkaloids than the leaf. Contains (−)-hyoscyamine and atropine. -Acts as a parasympathetic depressant with anticholinergic properties. -Used as a spasmolytic agent, decreases intestinal tone and secretions, induces passive mydriasis, and increases heart rate.
• Hyoscyamus (Henbane): Dried leaves and flowering tops of Hyoscyamus niger -Contains hyoscyamine, hyoscine, and atropine. -Used as a parasympatholytic, but rarely employed today. -Egyptian Henbane (Hyoscyamus muticus) has a higher alkaloid content, consisting largely of hyoscyamine. Used for alkaloid extraction.
• Stramonium (Datura stramonium): Dried leaves and flowering tops
  • Contains hyoscyamine.
  • Acts as an anticholinergic similar to belladonna. -Used as an ingredient in preparations inhaled for asthma relief.
• These drugs are used as mydriatics, antispasmodics, parasympatholytics, and to decrease secretions.

Cocaine Biosynthesis

• Cocaine: habit forming drug of Erythroxylum coca. -Phenylalanine is incorporated into cocaine, and the ecgonine moiety derives from ornithine and acetate. -Cocaine is the methyl ester of benzoyl ecgonine.

Quinoline Alkaloids

• Alkaloids include quinine, quinidine, cinchonine, and cinchonidine obtained from cinchona bark.
• Cinchona alkaloids possess two ring structures: quinoline and bicyclic quinuclidine.
• They have a basic skeleton of 9’-rubanol derived from ruban.

Basic Structures

• Quinoline consists of a benzene ring fused to pyridine
• Contain 4-methyl quinoline and quinuclidine.

Cinchona Alkaloids

• Quinine and quinidine are stereoisomers.
• Cinchonine and cinchonidine are stereoisomers.
• For cinchonine and quinidine, C8= R, C9 = S.
• For cinchonidine and quinine, C8 = S, C9 = R. Biosynthetic pathway is from geraniol, and tryptophan.

Identification Tests for Quinine

• Fluorescence Test: Gives blue fluorescence with oxygenated acid.
• Thalleioquin Test: Produces emerald green color with bromine water and ammonia solution.

Uses

• Cinchona: used in the treatment of malaria
• Quinine: used for malaria, as tonic, analgesic, in the treatment of cold.
• Quinidine: used to treat various cardiac arrhythmias -Found as salts (sulfate & gluconate) -Depresses myocardial excitability, conduction velocity & contractility.

Totaquine

• Mixture of total alkaloids containing quinine.
• Contains 70-80% of total alkaloids.
• Used as anti malarial & for cold but it cannot be used as cardiac depressant
• Usual dose 600mg.

Cinchonism

• Treatment with cinchona products results in symptoms.
• Symptoms include flushed and sweaty skin, ringing of the ears (tinnitus), blurred vision, impaired hearing, confusion, reversible high-frequency hearing loss, head ache, abdominal pain, rashes, dysphoria, nausea, vomiting and diarrhea.
• Ringing in the ears is a symptom of toxicity.

Isoquinoline Alkaloids

• Isoquinoline alkaloids are heterocyclic aromatic organic compounds.
• Isoquinoline and quinoline are benzo pyridines derivatives.

Types

• Benzylisoquinoline (BIQ) alkaloids: About 4000 BIQ alkaloids are known. - There are many important structural types. - Many BIQ alkaloids are important in medicine. - Others are highly toxic. - Some are used as arrow poisons. (papaverine and tubocurarine)
• Tetrahydrobenzylisoquinoline (THBIQ) alkaloids: The simplest alkaloids of this series are those in which the nitrogen-containing ring is completely saturated.
  • These alkaloids are found in almost all families that contain BIQ alkaloids. About 100 compounds of this type are known.
• The most important compound from a biosynthetic point of view is (+)-reticuline.
• Phenanthrene alkaloids: They are mainly found in papaveraceae family as morphine & related alkaloids.

Important Drugs and Alkaloids

• Ipecac (emetine), Hydrastis (hydrastine), Curare ((+)-tubocurarine), Berberis (berberine), Opium (morphine & related alkaloids), Sanguinaria (sanguinarine)

Ipecac

• Consists of dried rhizomes and roots of Cephaelis ipecacuanha or Cephaelis acuminate. -Yields at least 2% ether-soluble alkaloids. -Contains emetine, cephailine, and psychotrine. -Used in the treatment of drug overdose and poisoning -Emetine shows an emetic effect by stimulating the gastric mucous membranes and central medullary effect by stimulating chemoreceptor trigger zone. Cephaeline shows stronger emetic activity and higher toxicity than emetine. Emetine is also used as hydrochloride as a medicine for amoebic dysentery.

Hydrastis

• Consists of dried rhizomes and roots of Hydrastis canadensis
• Three alkaloids have been isolated from hydrastis: hydrastine, berberine, and canadine.
• Hydrastis yields at least 2.5% of anhydrous ether-soluble alkaloids.
• Hydrastine and berberine are used as astringents and antiinflammatory in inflammation of the mucous membrane like intestinal infection, vaginal infection, eye infection and urinary tract infection.
• Used for treatment of uterine hemorrhage, diarrhea and acne

Curare

• South American arrow poison from Strychnos castelnaei or S. crevauxii.
• Contains alkaloids and quaternary compounds, mainly (+)-tubocurarine.
• Exhibits a paralyzing effect on voluntary muscles by blocking nerve impulses to skeletal muscles.
• Tubocurarine is used as a skeletal muscle relaxant in surgical procedures without deep anesthesia.
• Also used to control convulsions of strychnine poisoning and of tetanus.

Berberis (Barberry)

• Sixteen isoquinoline alkaloids were isolated from Berberis vulgaris.
• Reported effects are anti-bacterial, anti-inflammatory, haemostatic, diuretic and vasodilator.
• Barberry can act as a very efficient remedy against bacterial, viral, fungal and parasitic infections.

Opium

• Air-dried milky exudates obtained by incising the unripe capsules of Papaver somniferum
• The cultivation of opium poppy is controlled internationally by the International Narcotic Control Board of the United Nations.

Cultivation of Opium

• Cultivated by planting in October.
• Each plant contains 5-8 poppy (fruit).
• The main constituents are 30 different alkaloids, the most important are Morphine, Codeine, Noscapine, Papaverine, and Thebaine.
• Opium also contains 3-5% of meconic acid which exists free or in combination with morphine, codeine & other alkaloids.
• Gives a red color in solution of ferric chloride (used for the detection of opium).

Classification of Opium Alkaloids

• Phanathrene: morphine, codeine, thebaine (act primarily on the CNS to produce depressant effect & they stimulate the contraction of the smooth muscles)
• Benzylisoquinoline: papaverine & noscapine (little action on the CNS but mainly act as antispasmodic)
• Phenylethylamine: narceine

Phanathrene Derivatives Structure

• Contain benzene ring, phenolic OH, N-CH3 (tertiary amine), and ether linkage.
• Changing OH at postion-3 to OCH3 yields codeine.
• Codeine & its salts are narcotic analgesics & antitussive. Morphine Phenanthrene derivative. Strong hypnotics & narcotics that induce nausea, vomiting, constipation, & habit forming. Ethyl morphine (dionine) - used in ophthalmology as analgesic less extent as codeine. Diacetyl morphine (heroin) - a drug of addiction Hydromorphone - a powerful narcotic analgesic & tends to strongly depress the respiratory mechanism

Other Opium Alkaloids

• Papaverine: smooth muscle relaxant.
• Noscapine: anti-tussive.
• Pantopon: Contains about 50% morphine, used because of synergistic effect.

Opioid vs. Opiate

• Opioid: psychoactive chemical that works by binding to opioid receptors.
• Opioid use decreases perception of pain, decreases reaction to pain as well as increased pain tolerance. Causes sedation, respiratory depression, constipation, and a strong sense of euphoria.
• Opiate: is properly limited to the natural alkaloids found in the resin of the opium poppy
• Classification of opioids: Natural opiates (morphine, codeine, and thebaine), Semi-synthetic opioids (hydromorphone), Fully synthetic opioids (pethidine, tramadol)

Sanguinaria (Blood Root)

• Consists of dried rhizomes and roots of Sanguinaria canadensis
• Contains the benzyl phenanthridine alkaloids sanguinarine, chelerythrine, protopine.
• Sanguinarine is mainly used as ingredient of compound white pine syrup
• Sanguinarine as colchicine, causes doubling of the chromosomes in the cell.

Biosynthesis of Isoquinoline Alkaloids

• Result from the condensation of a phenylethylamine derivative with a phenylacetaldehyde derivative, from phenylalanine or tyrosine.

Biosynthesis of Morphine

• Formed from two molecules of tyrosine.
• Comes from metabolite benzylisoquinoline.
• Thebaine is converted to codeine for analgesic affects.