alkaloids 1

Alkaloids 1

• Alkaloids originating from1-Capsaicinoides (Capsicum annuum [Solanaceae])Capsaicine:pungent, iritation on the skin, rubafecient in rheumatoid pain

2-Ephedrine, pseudoephedrine (Ephedra sinica)3-Cathine (Catha edulis)

CO2H

NH2

Phenylalanine

N

O

H

H3CO

HO

N

O

H

H3CO

HO OH

Capsaicin

Hydroxycapsaicin

Ephedrine

Ephedra sinica “ma huang”; Used in treatment of common cold, ↑BP and pulse, contraction of blood vessels,

bronchodilator, fat combustionPseudoephedrin vasoconstriction on mucous membranes, rhinitis, Herbal extasy, doping

NHCH3

OH

(-)-Ephedrine

Ephedra alkaloidsO

NH2

(-)-Cathinone

L-Phe

O

O

Diketon

TA

NHCH3

OH

NHCH3

OH

NH2

OH

NH2

OH

N(CH3)2

OH

N(CH3)2

OH

(-)-Ephedrine(+)-Pseudoephedrine

(-)-Norephedrine (+)-Norpseudoephedrine (Cathine)

(-)-N-methylephedrine(+)-N-Methylpseudoephedrine

NH2

(+)-Amphetamine (Amfetamine)

Khat tea: Catha edulis (Celastraceae)Leaves: Flav., vol. oils, cathedulins, tannins, cathinone, cathine,….Young leaves: cathinone;↓hunger and fatigue, increased alertness,

general excitement, ↑self-confidence, talkativeness, “constant mild high”

AE: inflammation of oral mucosa, gastric disturbances, anorexia, hypertension, impotence

NH2

OH

(+)-Norpseudoephedrine (Cathine)

O

NH2

(-)-Cathinone

NH2

(+)-Amphetamine (Amfetamine)

NHCH3

OCH3

O

O

(MDMA) 3,4-methylene dioxyamphetamine = Ecstasy

Alkaloids 2

• Alkaloids originating from-Adrenaline, noradrenaline-Mescaline --Isoquinoline alkaloids---Benzylisoquinoline alkaloids: Opium alkaloids---Bis-benzyl-isoquinoline alkaloids:Tubocurarin---Terpenoid tetrahydro-isoquinoline alkaloids:

Ipecac alkaloids (Emetine, cephaeline)

CO2H

HO

NH2

Tyrosine

Alkaloids 2• Alkaloids originating fromAdrenaline

CO2H

HO

NH2

Tyrosine

CO2H

HO

NH2

CO2H

HO

NH2

HO

O2

HONH2

HO

HONH2

O2

HONHCH3

HO

OH

HONH2

HO

OH

Tyrosine Tyramine

L-DOPA Dopamine

Noradrenaline = Norepinephrine

Adrenaline= Epinephrine

Tyrosine hydroxylase +Tetrahydrobiopterin

Ascorbate

Mescalin and Lophophora williamsii (Cactaceae)

• Mescal buttons, South American Indians, religious rituals as hallucinogenic [unusual colored hallucinations, flashing lights, euphoria,disturbes normal mental functions. Psychotomimetic]

HONH2

HO

HONH2

MeO

MeONH2

MeO

OMeDopamine

Mescaline

Alkaloids 3Alkaloids originating from

Colchicine occurs in the seeds and corms; non-basic alkaloid;• Anti-inflammatory; acute attacks of gout; cytotoxic; anti-mitotic• Tox. Symptoms: swallowing difficulties, abdom. pain, ↓BP, muscle

cramp, resp. difficulties; Death: resp. arrest, CV collapse• Toxic dose: 10mg; above 40 mg death within 3 days; suicidal

attempts

CO2H

NH2

Phenylalanine

CO2H

HO

NH2

Tyrosine

C

B N

O

CH3

O

H3CO

H3CO

H3CO

H3CO

H

A

(-)-Colchicine

7-membered ring

Tropolone ring

1

35

7

10

128

Isoquinoline alkaloids and Benzylisoquinoline alkaloids

• Basic structures:

NH

Isoquinoline

12

345

6

7

8

NH

Tetrahydroisoquinoline

12

345

6

7 8

NH

Benzyltetrahydroisoquinolines

12

3

456

7 8

1'2'

3'

4' 5' 6'

N

Benzylisoquinolines

12

3

456

7 8

1'2'

3'

4' 5' 6'

Papaver somniferum (Papaveraceae)

• Opium: alkaloid richest drug• Alkaloids: 20-30%, meconic acid: ~5%; lactic acid: 1-2%;

other acids, enzyms, proteins, resins, fats• Morphine alkaloids: thebaine, codeine, morphine• Benzylisoquinoline alkaloids: Papaverine• Phthalidisoquinoline alkaloids: Noscapine (narcotine)• Several semisynthetic derivatives: Ethylmorphine,

diacetyl morphine (heroine), apomorphine, hydromorphone, hydrocodone, cotarnine,….

O

OH

HO2C CO2H

O

Meconic acid

Important opium alkaloids

Papaverine

• Thebaine Codeine Morphine

N

H3CO

H3CO

H3CO

H3COPapaverine

6

7

3'

4'

1

45

1'

8

Opium and morphine• Opium: CNS stimulant, analgesic, hypnotic, narcotic, stimulating /

depressing, checks excess peristalsis, pupil contraction; • Crude opium: ~10% morphine (analgesic, sleep inducer, cough treatment)• Powdered/granulated opium: • Laudandum (opium tincture): analgesic, narcotic• Camphorated opium (paregoric): antiperistaltic, diarrhea, dysentery; cough prep.• Dower’s powder (+ ipecac): diophoretic, influenza; sedative ;

• Morphine: mental detachment, tolerance, addiction, withdrawal symptoms• CNS: drowsiness, analgesia, euphoria Pupil: miosis Respiration: depressant; respiratory arrest GI: Stomach: HCl↓, small intestine: Biliary and pancreatic juices ↓

(delayed food digestion), large intestine: peristaltic waves↓, tone↑ (spasm, constipation)

Bronchi: large doses (bronchconstriction), Nausant and emetic effects, habit formation, …..

Codeine, thebaine, noscapine and papaverine• Codeine (methylmorphine): most widely used opium

alkaloid, antitussive and narcotic analgesic in the liver [-CH3]; (1/10 the potency of morphine); less toxic, less habit formation, little euphoria; constipation on long term use

• Thebaine: used primarily for the semi-synthetic production of other drugs, incl. codeine;

• Papaverine (not morphinane!): Smooth muscle relaxant, spasmolytic, little analgesic effect; male impotence!

• Noscapine (not morphinane!): Antitussive and cough suppressant, no analgesic or narcotic action; teratogenic!; antitumor action

• Papaveratum is a mixture of opium alkaloid: morhine (85.5%), codeine (7.8%), papaverine (6.7%); pain relief during surgery; may be combined with hyoscine

Semisynthetic and synthetic derivatives of morphine and thebaine

1-Morphine derivatives: codeine, pholcodine, ethylmorphine, hydromorphone, apomorphine, heroine, nalorphine; dextrometorphan, pentazocine, pethidine, fentanyl, methadone, tramadol

Morhine antagonist: naloxone

2-Thebaine derivatives: Codeine, etorphine, buprenorphine, oxymorphone :nalbuphine, naloxone, naltrexone

Bis-benzyl-isoquinoline alkaloids: Curare• Dried extract of barks and stems applied to various South American arrow

poisons1-Menispermaceae curare: Chondrodendron tomentosum : Bis-benzyl –THIQ

alkaloids; 4-7% alkaloids; d-tubocurarine2- Loganiaceae curare: Strychnos spp. : Indol alkaloids3-Mixture of both plants“Monkey test”; “head drop test” d-tubocurarine: H2O-sol., monoquaternary NH4-salt;

Paralysis, relaxation of voluntary muscles, competes with acetylcholine at nicotinic receptors; death: muscles of respiration stops to operate; treatment: artificial respiration and specific antidotes: anti-acetylcholine-esterase drugs: Physostigmine, neostigmineUses: Parkinson’s disease, MS, tetanus; skeletal muscle relaxant, surgery

Synth. Analogues: deca-, suxa-methonium; atracurium, vencuronium

Terpenoid tetrahydro-isoquinoline alkaloids Radix ipecacuanha

• Cephaelis ipecacuanha, C. acuminata (Fam. Rubiaceae)• Major alkaloids: emetine and cephaeline• Minor alkaloids: psychotrine and O-methyl-psychotrineIpecac: high doses: emetic; small doses: expectorantEmetine: antiaemebic, anti-protozoan, amebic dysentery,

expectorant, antiviral, antitumor; O-methylpsychotrine: AIDS (inhibition of HIV reverse transcriptase)

psychotrine O-methyl-psychotrine