PHG 322PHARMACOGONSY IILECTURE 3PRESENTED BYASSISTANT PROF. DR. EBTESAM ALSHEDDI

الرحيم الرحمن الله بسم

III. Alkaloids of the Isoquinoline group

Ipeca Opium Curare

Raw opium

• Raw opium: is the air dried latex obtained by the incisions from the unripe capsules of Papaver somniferum (Papaveraceae).

• Opium is the source of many alkaloids, including morphine, thebaine, codeine, papaverine, and noscapine.

• Morphine is the predominant one.

CALIFORNIA POPPIES

Papaver spp

Do not contain morphine or codeine,but like all poppies have papaverine

(the “poppy alkaloid.)”

OPIUM POPPY

Papaver somniferum

Opium alkaloids occur naturally combined with specific acid (meconic acid).Occurs only in opiumSpecific test:Meconic acid + FeCl3 gives purplish red colourNot destroyed by dilute HCl (c.f. from ferric acetate and formate)Unaffected by addition of HgCl2 (c.f. from thiocyanate)

O

O

OH

COOHHOOC

CLASSIFICATION Natural opiates: are alkaloids contained in the latex of opium as morphine, codeine, and thebaine.

Semi-synthetic opioids: created from the natural opiates, such as heroin, oxycodone, and hydrocodone are derived from morphine, codeine, and thebaine.

Fully synthetic opioids: such as pethidine, methadone, tramadol.

Endogenous opioid peptides, produced naturally in the body, such as endorphins, enkephalins, dynorphins, and endomorphins.

Opium alkaloids are subclassified into 3 groups:

Benzylisoquinoline alk.

Phenylethylamine alk.

Phenanthrene alk.

8

BENZYLISOQUINOLINE:Papaverine

Properties:

It is a weak base and is optically inactive.

Tests for identificationWarren's test (specific for papaverine):

Papaverine + crushed crystal of KMnO4

+ Marqui's reagent green color blue.

Uses:

Papaverine possesses smooth muscle relaxant activity. It is used as antispasmodic for GIT spasms, clots and in bronchial asthma in a dose up to 600 mg of papaverine HCl daily.

N

OCH3

OCH3

H3CO

H3CO

Phenylalkylamines:Narceine

Properties:

It is a tertiary Alkaloids. Narceine is an amphoteric alkaloid since it contain a carboxylic group.

N

O

O

C O

CH3

CH3

COOH

OCH3

OCH3

OCH3

PHENANTHEREN GROUP:Morphine:

Properties:Morphine is levorotatory, insoluble in water, sparingly soluble in ethanol (1:250) and chloroform (1:1500), practically insoluble in ether and benzene.

It contains 2 OH groups, one is a phenolic at C-3 (gives a soluble phenate with alkali) and the other is a 2ry alcoholic at C-6.

RO

HO

NCH3H

O

R= H MorphineR= CH3 Codeine

A

B

C

DE

3

6

TESTS FOR IDENTIFICATION:Tests due to phenolic properties: 1- Morphine gives a blue color with FeCl3.

2- Nitrous acid test: solution of morphine in dilute HCl + NaN02 + NaOH red color.

3- Morphine + dil H2SO4 + HI→ I2 give violet colour when dissolve in CHCl3

Tests with alkaloidal color reagents:1- Liebermann' s reagent black color.

2- Mandalin's reagent bluish-gray color.

3- Marquis' reagent violet color.

4- HNO3 → red colour convert to yellow on heating.

USES:Morphine act as a narcotic analgesic (reduce pain & induce sleep) in a dose of 5-20 mg of morphine hydrochloride, sulfate or tartrate, administered orally or parentrally, every 4 hours.

Used before and after surgical operations and to terminally ill cancer patients.

Suppress peristaltic movement so stops diarrhea.

Adverse Effects:Two major problems are associated to morphine use:

Addiction and Tolerance.

Morphine

O

HOH

NH

CH3

HO1

23

4

5

6

7

8

9

10

11

12

1314

15 16

Morphine (Astramorph)

HO- Group is needed for activity

HO- Group not important to activity

Codeine:

Properties:

It is soluble in H2O, boiling H2O, ethanol, CHCl3 and ether, (c.f. morphine).

Codeine is non Phenolic.

Test: Codeine + concentrated H2SO4 + FeCl3, warm in water bath bluish violet color + HNO3 Red color.

Uses:

It has less narcotic analgesic than morphine.

It is mainly used as antitussive.

RO

HO

NCH3H

O

R= H MorphineR= CH3 Codeine

A

B

C

DE

3

6

Codeine

O

HOH

NH

CH3

HO1

23

4

5

6

7

8

9

10

11

12

1314

15 16

Morphine (Astramorph)

HO- Group is needed for activity

HO- Group not important to activity

O

HOH

NH

CH3

CH3O

Codeine (5X LESS potent than morphine)

Inefficiently converted to HO group in the liver

Thebaine

Thebaine (paramorphine) is an opiate alkaloid. A minor constituent of opium, thebaine is chemically similar to both morphine and codeine, but produces stimulatory, with strychnine-like convulsions, rather than depressant effects. Thebaine is not used therapeutically, but is converted industrially into a variety of compounds including oxycodone, oxymorphone, nalbuphine, naloxone, naltrexone, buprenorphine and etorphine.

O

CH3O

NH

CH3

CH3O

SEMI-SYNTHETIC DERIVATIVES OF MORPHINE:

Heroin

It is the diacetyl derivative of morphine. It has no any medical applications but it is one of the most dangerous abused substance.

Morphine is easily acetylated to diacetylmorphine using acetic anhydride.

CH3

CO

CCH3

O O

morphine

Heroin is more potent than morphine (it takes less for the same effect), lasts longer, and is more addicting.

Apomorphine

Obtained by heating morphine with coc. HCl in sealed vials. During this reaction rearrangement and elimination of water takes place. Apomorphine is used in the treatment of Parkinson’s disease and erectile dysfunction.

+ HCl, Δmorphine

Ether bridge opening (ring E):

Resulted in group of compounds called morphinans. Synthetic morphinans are racemic compounds. Only the levo isomers have analgesic activity. Levorphanol is 8 times as active as morphine. The dextro isomers as dextromethorphane lack the CNS and analgesic effects, however, they are used as cough suppressants.

RO

NCH3H

R= H (-) Levorphanol RP=8R= CH3 (+) Dextromethorphan

RO

HO

NCH3H

O

R= H MorphineR= CH3 Codeine

A

B

C

DE

3

6

The C-6 Hydroxyl group and ring c modifications:Removal or derivitization of the alcoholic hydroxyl group at C-6 increase

lipophilicity and consequently the analgesic activity.

Reduction of the 7,8 double bond, oxidation of C-6 hydroxyl and addition of OH group at C-14 all increase the activity.

HO

R

NCH3H

O

HO

NCH3R

O

HO

HO

NCH3H

O

O

R=H Hydromorphone RP=5-6R=OH Oxymorphone RP=10Dihydromorphine

14

R=H 6-Deoxymorphine RP=10R=OCH3 6-Methoxymorphine RP=5R=OC2H5 6-Ethoxymorphine RP=2.5R=OCOCH3 6-MAM RP=4.2

The C-3 Hydroxyl group:

Etherification of this phenolic OH decrease the analgesic activity and the compounds are used mainly as antitussive e.g. Codeine and Pholcodine.

C2H4O

HO

NCH3H

O

NO

Pholcodine

Similar synthetic manipulations make hydrocodone more potent than codeine

O

H

NH

CH3

CH3O1

23

4

5

6

7

8

9

10

11

12

1314

15 16

Hydrocodone(much more potent than codeine)

O

Hydrocodone or dihydrocodeinone (marketed as Vicodin, Anexsia, Dicodid, Hycodan, Hycomine, Lorcet, Lortab (or Loritab), Norco, Novahistex, Hydroco, Tussionex, Vicoprofen, Xodol) is a semi-synthetic opioid derived from two of the naturally occurring opiates, codeine and thebaine. Hydrocodone is an orally active narcotic analgesic and antitussive. Sales and production of this drug have increased significantly in recent years, as have diversion and illicit use. Hydrocodone is commonly available in tablet, capsule and syrup form.

Oxycodone

O

HOH

NH

CH3

HO1

23

4

5

6

7

8

9

10

11

12

1314

15 16

Morphine (Astramorph)

HO- Group is needed for activity

HO- Group not important to activity

O

OOH

NH

CH3

CH3O

-OH group increases potencyOxycodone (Percocet)(equal to morphine in potency)

CH3 group reduces potency

Reduced C=C

oxidized OH

Oxycodone• Oxycodone is a potent and potentially addictive

opioid analgesic medication synthesized from thebaine. Its name is derived from codeine - the chemical structures are very similar.

• It is effective orally and is marketed in combination with aspirin (Percodan, Endodan, Roxiprin) or paracetamol/acetaminophen (Percocet, Endocet, Roxicet, Tylox) for the relief of pain. More recently, ibuprofen has been added to oxycodone (Combunox).

N atom substitution: Methyl group in nitrogen resulted in compounds with analgesic effects. Ethyl morphine is also analgesic. Compounds with 3- 5 carbons alkyl group on nitrogen are antagonists. More than 5 carbons the compounds again are analgesic.

O

OH

NH

CH2

HO1

23

4

5

6

7

8

9

10

11

12

1314

15 16

HC

Naloxone

CH2O

O

HOH

NH

CH2

HO1

23

4

5

6

7

8

9

10

11

12

1314

15 16

HC

Nalorphine

CH2

O

OH

NH

CH2

HO1

23

4

5

6

7

8

9

10

11

12

1314

15 16

Naltrexone

O

3 -CURARE ALKALOIDSOccurrence:Curare or South American arrow poison is the dried crude extract, obtained mainly from Chondrodendron tomentosum (Menispermaceae) and certain Strychnos species, (Loganiaceae).

Curare contains several alkaloids (4-7%), the most important is d-tubocurarine.

N

OH

MeO

N

H

H

Me

OMe

O

OH

O

Me

+Me

Properties: d-tubocurarine (4ary alkaloid) is freely soluble in H2O. It is a phenolic

dextrorotatory alkaloid. It is a bis-benzyltetrahydroisoquinoline alkaloid.

Tests: Saturated aqueous solution + FeCl3 faint green color green color.

Solution of the alkaloidal HC1 + Na2CO 3 yellow brown precipitate.

Uses: Tubocurarine chloride is mainly used by i.m. or i.v. routes as

skeletal muscle relaxant.

It is used to control and reduce convulsions of strychnine poisoning and of tetanus.

It is used as a diagnostic aid in myasthenia gravis.