Opium AlkaloidsOpium Alkaloids Occurrence:Occurrence: Opium is the air-dried Opium is the air-dried milky exudatemilky exudate, or latex, obtained by incising the , or latex, obtained by incising the

mature unripe capsules of the mature unripe capsules of the opium poppyopium poppy Papaver somniferumPapaver somniferum (Fam. (Fam. Papaveraceae). Papaveraceae).

Sources:Sources: Turkey- India- Europe.Turkey- India- Europe.

Illegal Production:Illegal Production: Afganistan- Pakistan- Iran- Purma, Laos, Thiland.Afganistan- Pakistan- Iran- Purma, Laos, Thiland.

Constituent of Opium:Constituent of Opium:Opium contain more than 40 alkaloids usually combined with a specific Opium contain more than 40 alkaloids usually combined with a specific

acid (acid (Meconic acidMeconic acid) or with other acids e.g. sulfuric and acetic acids.) or with other acids e.g. sulfuric and acetic acids.

Tests for identification of Meconic acid:Tests for identification of Meconic acid:

Meconic acidMeconic acid + + FeClFeCl33 gives gives purplish red colourpurplish red colour

Not destroyed by dilute HCl (c.f. from ferric acetate and formate)Not destroyed by dilute HCl (c.f. from ferric acetate and formate) Unaffected by addition of HgClUnaffected by addition of HgCl22 (c.f. from thiocyanate) (c.f. from thiocyanate)

O

O

OH

COOHHOOC

Classification:Classification:

Opium alkaloids can be subclassified into 3 main groups with Opium alkaloids can be subclassified into 3 main groups with different basic nuclei:different basic nuclei:

Phenanthrene alkaloids Phenanthrene alkaloids e.g. e.g. morphine and codeine.morphine and codeine.

Benzylisoquinoline alkaloidsBenzylisoquinoline alkaloids e.g. e.g. papaverinepapaverine and and noscapine noscapine (narcotine). (narcotine).

Phenylethylamine alkaloids Phenylethylamine alkaloids e.g. e.g. narceinenarceine

Phenantheren group:Phenantheren group: Morphine:Morphine:

Properties:Properties: MorphineMorphine is is levorotatory levorotatory, insoluble in water, sparingly soluble in , insoluble in water, sparingly soluble in

ethanol (1:250) and chloroform (1:1500), practically ethanol (1:250) and chloroform (1:1500), practically insoluble in etherinsoluble in ether and benzeneand benzene..

It contains It contains 2 OH groups2 OH groups, , oneone is a is a phenolic phenolic at C-3 (gives a soluble at C-3 (gives a soluble phenate with alkali) and the other is a 2ry alcoholic at C-6.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 for identification: Tests due to phenolic propertiesTests due to phenolic properties:: 1- Morphine gives a 1- Morphine gives a blue colorblue color with with FeClFeCl33..

2- Nitrous acid test2- Nitrous acid test: solution of : solution of morphinemorphine in dilute HCl + in dilute HCl + NaN0NaN022 + + NaOHNaOH red color red color..

3- Morphine + dil H3- Morphine + dil H22SOSO44 + HI + HI→ I→ I22 give give violetviolet colour when colour when dissolve in CHCldissolve in CHCl33

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

2- Mandalin's reagent 2- Mandalin's reagent bluish-gray colorbluish-gray color..

3- Marquis' reagent 3- Marquis' reagent violet colorviolet color..

4- HNO4- HNO33 →→ red colourred colour convert to convert to yellowyellow on heating. on heating.

Uses:Uses: MorphineMorphine act as a act as a narcotic analgesicnarcotic analgesic (reduce pain & induce sleep) in (reduce pain & induce sleep) in

a dose of a dose of 5-20 mg5-20 mg of morphine hydrochloride, sulfate or tartrate, of morphine hydrochloride, sulfate or tartrate, administered orally or parentrally, every 4 hours. administered orally or parentrally, every 4 hours.

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

Suppress peristaltic movement so stops diarrhea.Suppress peristaltic movement so stops diarrhea.

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

Addiction and Tolerance.Addiction and Tolerance.

Codeine:Codeine:Properties:Properties:

It is It is soluble in Hsoluble in H22OO, boiling H, boiling H22O, ethanol, O, ethanol, CHClCHCl33 and ether, (c.f. and ether, (c.f.

morphinemorphine).). Codeine is non Phenolic.Codeine is non Phenolic.

Test:Test: CodeineCodeine + concentrated + concentrated HH22SOSO44 + + FeClFeCl33, warm in water bath , warm in water bath

bluish violetbluish violet color color + + HNOHNO33 RedRed color color..

Uses:Uses: It has less narcotic analgesic than morphine.It has less narcotic analgesic than morphine. It is mainly used as antitussive.It is mainly used as antitussive.

RO

HO

NCH3H

O

R= H MorphineR= CH3 Codeine

A

B

C

DE

3

6

Benzylisoquinoline:Benzylisoquinoline: PapaverinePapaverine

Properties:Properties:It is a weak base and is optically inactive.It is a weak base and is optically inactive.

Tests for identificationTests for identification Warren's test Warren's test (specific for papaverine):(specific for papaverine):

Papaverine + crushed crystal of KMnOPapaverine + crushed crystal of KMnO44

+ Marqui's reagent + Marqui's reagent green color green color blue. blue.

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

N

OCH3

OCH3

H3CO

H3CO

Semi-synthetic derivatives of Morphine:Semi-synthetic derivatives of Morphine:

HeroinHeroin

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

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

N CH3

HO

HO

Apomorphine

H3COCO

H3COCO

NCH3H

O

Heroin

N atom substitution:N atom substitution: Methyl group in nitrogen resulted in compounds with analgesic effects. Methyl group in nitrogen resulted in compounds with analgesic effects.

Ethyl morphine is also analgesic. Compounds with 3- 5 carbons alkyl Ethyl morphine is also analgesic. Compounds with 3- 5 carbons alkyl group on nitrogen are antagonists. More than 5 carbons the compounds group on nitrogen are antagonists. More than 5 carbons the compounds again are analgesic. again are analgesic.

Ether bridge opening (ring E):Ether bridge opening (ring E): Resulted in group of compounds called morphinans. Synthetic Resulted in group of compounds called morphinans. Synthetic

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

RO

NCH3H

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

The C-3 Hydroxyl group:The C-3 Hydroxyl group:

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

C2H4O

HO

NCH3H

O

NO

Pholcodine

The C-6 Hydroxyl group and ring c modifications:The C-6 Hydroxyl group and ring c modifications:Removal or derivatization of the alcoholic hydroxyl group at C-6 increase Removal or derivatization of the alcoholic hydroxyl group at C-6 increase lipophilicity and consequently the analgesic activity.lipophilicity and consequently the analgesic activity.

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

Phenylalkylamines:Phenylalkylamines: NarceineNarceine Properties:Properties:

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

N

O

O

C O

CH3

CH3

COOH

OCH3

OCH3

OCH3