Quinoline Alkaloids

Quinoline Alkaloids

• Any alkaloid with a quinoline skeleton (1-azanaphthalene or benzo[b]pyridine) is a quinoline alkaloid; quinine is an example
• Cinchona alkaloids are the only therapeutic alkaloids in this group, others are poisons
• Quinoline alkaloids can be sourced from the bark of different Cinchona species (family Rubiaceae), such as Cinchona officinalis
• Other genera within the same family, such as Remijia, also contain quinoline alkaloids
• Cinchona contains 6-10% alkaloids (~24-30 alkaloids); quinine, quinidine, cinchonine, and cinchonidine are key, differing by methyl group presence and stereochemistry
• They are in the bark as salts of cinchotannic acid and quinic acid
• All quinoline alkaloids share a general structure: a quinoline ring (less basic) attached via a hydroxymethylene group to a quinuclidine ring (more basic) containing a vinyl group
• Quinine and quinidine are enantiomeric pairs, as are cinchonidine (for quinine) and cinchonine (for quinidine); stereochemistry varies at positions 8 and 9
• Stereochemistry: quinine (cinchonidine) is S,R, and quinidine (cinchonine) is R,S

Crude Cinchona

• Cinchona possesses antimalarial and tonic properties
• Totaquine, a crude cinchona alkaloid preparation, is used as an antimalarial agent; its activity is due to quinine

Quinine

• Levo (-) stereoisomer of quinidine, used as salts (sulfate, bisulfate, hydrochloride, dihydrochloride)
• Treats chloroquine-resistant malaria strains
• It is given alongside primaquine for relapsing vivax malaria
• Some use it as an analgesic for nocturnal leg cramps

Quinidine

• Dextro (+) stereoisomer of quinine, used as sulfate (sparingly soluble) and gluconate (readily soluble) salts
• Used as a Class 1 anti-arrhythmic agent
• IV quinidine gluconate may treat P. falciparum malaria

Isoquinoline alkaloids

• Isoquinoline alkaloids are derived from quinoline alkaloids
• Isoquinoline alkaloids have an isoquinoline skeleton; examples include papaverine and morphine (which features a phenanthrene nucleus)
• The isoquinoline backbone is biosynthesized from the aromatic amino acid tyrosine
• Isoquinoline is a colorless, hygroscopic liquid that is slightly soluble in water but very soluble in ethanol, acetone, and ether
• Isoquinoline is a weak base with a pKa of 8.6
• Isoquinoline alkaloids are important in medicine, with several available as drugs

Medicinal Uses of Isoquinoline Alkaloids

• Dimethisoquin: Anaesthetic
• Quinapril: Antihypertensive agent
• 2,2'-hexadecamethylenediisoquinolinium dichloride: Topical antifungal agent
• Papaverine: Vasodilator
• Morphine: Narcotic analgesic

Opium Alkaloids

• Opium is the dried latex from incisions of Papaver somniferum capsules (fruits), family Papaveraceae
• It contains over 40 alkaloids; the most important ones are isoquinolines (e.g., papaverine, narcotine) and phenanthrenes (e.g., morphine, codeine, thebaine)
• In tissues, they are salts of common or specific acids like meconic acid

Papaverine

• Found in opium at ~1% yield
• It is mainly used to treat spasms and erectile dysfunction
• Can be used as a cerebral/coronary vasodilator and smooth muscle relaxant in microsurgery
• In pharmaceutical preparations, it is used as a water-soluble salt form (e.g., HCl)

Side Effects and Derivatives of Papaverine

• Side effects: polymorphic ventricular tachycardia, constipation, elevated transaminase levels, hyperbilirubinemia, vertigo
• Derivatives were prepared to reduce side effects:
  • Ethaverine: ethoxy derivative that is 3x more active with fewer side effects
  • Dioxyline: vasodilator

Narcotine (Noscapine)

• 8-methoxy hydrastine, found in opium at 9% yield
• Has no narcotic effect
• Used medicinally as a base and non-salt form
• Used medicinally as a cough suppressant (anti-tussive), as active/safe as codeine

Ipecacuanha Alkaloids

• Found in the roots and rhizomes of Cephaelis ipecacuanha (family Rubiaceae)
• Four important alkaloids: psychotrine, cephaeline, emetine, psychotrine methyl ether
• Except for emetine, all are toxic and not used clinically
• However, those 3 can be converted into the medicinally active emetine, using reduction and methylation
• Emetine is used as HCl salt (injection) or dichloride salt (tablets)
• It is antiamebic, emetic, and expectorant

Curare Alkaloids

• One of the most poisonous natural neurotoxins
• D-tubocurarine is the most important curare alkaloid and is sourced from the bark of the South American plant Chondrodendron tomentosum
• Previously used as arrow poison for hunting
• D-tubocurarine HCl salt is a skeletal muscle relaxant, specifically a neuromuscular blocking agent to induce muscle relaxation during surgery
• Some used it to control strychnine convulsions

Phenanthrene Alkaloids

• The second class of opium alkaloids, with key members being morphine, codeine, and thebaine

Morphine

• The only phenolic (free phenolic OH group) alkaloid in this class
• It is the major bioactive constituent of opium poppy seeds (~3-25% of opium)

Isolation

• Morphine is the only opium alkaloid with an acidic phenolic OH group and a basic 3ry amino group
• Opium powder is soaked in lime water Ca(OH)2 for 24 hrs, where morphine forms a water-soluble Ca salt, also precipitating other nonphenolic alkaloids as free bases
• Other alkaloids are extracted using organic solvents, leaving Ca salt of morphine in the aqueous layer
• Adding NH4Cl solution to the aqueous layer, the pH should be between 8-9
• This will convert the morphine Ca salt to a free base, which precipitates
• The precipitate (free morphine base) is filtered off and recrystallized

Morphine Properties

• It is a solid, white, optically active (l-), and water-insoluble
• Soluble in alkali solutions and alcohol
• Morphine, like other opium constituents (opiates) such as heroin, acts directly on the CNS to relieve pain
• Morphine is a narcotic analgesic, which means it increases tolerance to pain and decreases perception to external stimuli
• It is also used for post-surgical and chronic pain (e.g., cancer pain) and as an adjunct to general anesthesia
• It is a standard narcotic analgesic to which other analgesics are compared
• Medicinally used as morphine HCl salt and morphine sulfate salt
• Side effects: addiction and habituation, mental performance impairment, euphoria, drowsiness, loss of appetite, constipation, lethargy, and blurred vision

Chemical Conversions of Morphine

• 3-MAM (3-monoacetylmorphine): 50%
• Heroin (diamorphine): 200%
• 6-MAM (6-monoacetylmorphine): 400%
• Codeine (3-methyl morphine): 15%
• Apomorphine: 0%
• Dionin (3-ethyl morphine): 10%
• All acetyl derivatives of morphine are not used medicinally because they are more toxic and cause faster addiction than morphine

Codeine

• It is 3-methylmorphine, representing 0.3 - 5% of opium

Thebaine

• Obtained via opium extraction or morphine methylation
• Nonphenolic, solid, water-insoluble, and optically active (l-) alkaloid
• Medicinal uses: cough suppressant (anti-tussive) and a weak narcotic analgesic (just 15% of morphine)
• Also is used as codeine phosphate
• Has 2 OCH3 groups on C-3 and C-6, and conjugated diene in ring C
• Solid, optically active (l-) alkaloid
• Has neither narcotic nor analgesic effects
• Can cause convulsions
• Used to prepare another opioid called demethylated oripavine, which is the parent compound from which a series of semisynthetic opioids are derived

Apomorphine

• Prepared via morphine or codeine dehydration
• Used as HCl salt as a safe emetic drug; induces emesis centrally by stimulating the chemoreceptor trigger zone (CTZ)

Nalorphine and Naloxone

• Semisynthetic derivatives prepared from morphine: N-allyl normorphine derivatives
• Used as HBr salts as opiate antagonists during opiate overdose incidents

Structure-Activity Relationship (SAR) of Morphine

• Several derivatives have have the same narcotic analgesic effect of morphine, without the tenancy for addiction,
• All morphine-like analgesics must have:
• A tertiary nitrogen with a reasonably small group, e.g., CH3
• A central quaternary carbon atom (C-13)
• A 2-carbon chain (ethyl group) separating the central carbon from the N atom

Hydroxyl Groups

Masking the 3-OH group (phenolic one) suppresses activity (codeine is only 15% of morphine activity), masking 6-OH group (the alcoholic one) dramatically increases the narcotic activity (heterocodeine is 600% of morphine activity) Acetylation of 3- and 6-OH groups (heroin) increase activity

Additional Notes

• Ether linkage is unessential for activity; N-methylmorphinan has analgesic activity
• Morphine should be optically active (L-isomer is the active form) to show narcotic analgesic activity; Racemic mixture of morphine (D- and L-) is not active