Md. Imran Nur ManikLecturer

Department of PharmacyNorthern University Bangladesh

Natural products and

secondary metabolites

AlkaloidsSyllabus for Alkaloids: alkaloids as pharmaceutical raw materials, opium and its analogue, synthesis of ephedrine, clinical comparison of ephedrine and epinephrine.

Alkaloids may be defined as basic nitrogenous compounds which occur abundantly in the plant kingdom. They contain one or more nitrogen usually in a heterocyclic ring and have a marked physiological action on man & animals. The nitrogen may exist as primary (1° amines), secondary (2° amines) or tertiary (3° amines) amine. These compounds are basic but the degree of their basicity depends on the structure of the molecule and presence and location of other functional groups.

Alkaloids as pharmaceutical raw materials:

Alkaloids are natural products. They are the secondary metabolites of plant. Their structure is diverse varying from simple to very complex structure and their activity is also highly selective based on the structure. For example-

The difference between morphine and codeine is that codeine contains a methoxy group in place of phenolic hydroxyl group. Morphine is an analgesic and it is 10 times more potent compare to codeine. But codeine is mainly used as anti-tussive drug. It has mild analgesic.

Again thebaine has structure similar to morphine and codeine (both the hydroxyl groups are replaced by methoxy groups). But thebaine is neither analgesic nor anti-tussive and it is mainly used as CNS stimulant.

Thus we can see that the simple molecular modification of principle compound can give variation of pharmacological action and thus suit the need of different diseases. So it is easily understandable that nature can give us idea of designing drug molecules for different indications.

Opium alkaloids:Opium:It is the air dried milky exudates obtained by incising the unriped capsules of poppy plant (Papaver somniferum Linn. of Papaveraceae family).The plant poppy is an annual herb with large, showy, solitary flowers having colour of pink to purple.

Geographical source:The plant is indigenous to Asia Minor. The plant poppy is cultivated in many

countries but legal opium production is not permitted in all countries.

Constituents:More than 30 alkaloids are found in opium. The two principle types of

alkaloids present in opium are –1.Alkaloids containing partially hydrogenated phenanthrene nucleus: Examples include morphine, codeine, thebaine etc which act primarily on the CNS and produce stimulation or depression as well as smooth muscle contraction. 2. Alkaloids having 1-benzyl-isoquinoline structure: Example Narcotine, Papaverine. They have little CNS action.

The most important are the alkaloids1.Morphine: It is the most important opium alkaloid. It is a phenanthrene derivative containing an alcoholic and phenolic OH group. Morphine and its salts occur as white silky crystals, odorless and having a bitter taste. They are classified as narcotic analgesics and are strong hypnotic and narcotic. Their use tends to induce habit formation as well as common side-effects as nausea, vomiting and constipation.

2.Codeine: It is the most widely used opium alkaloid. It is obtained from opium, or by methylation of morphine or by appropriate reduction and demethylation of thebaine. If methyl group replaces the hydrogen of phenolic OH in morphine it becomes codeine. The drug and its salts are narcotics and antitussives. They are used as sedatives especially in allaying coughs. Its action is similar to that of morphine but is less toxic.

Heroin: Diacetylmorphine or heroine is formed by acetylation of morphine, where the hydrogen atoms of both the phenolic and alcoholic hydroxyl groups are replaced by acetyl groups. Its action is similar but more pronounced than that of morphine. Due to its potency and the danger of habit formation it is not used in medicine.

3. Noscapine4. Thebaine5. Papaverine Also contains alkaloids like: i. Narceine, ii. Protopine, iii. Laudanine, iv. Codamine, iv. Cryptopine, v. Lanthopine , vi. Meconidine

Introduction: Ephedrine is an Alkaloidal amine having sympathomimetic action. Its action is similar to adrenaline but there are some differences.Ephedrine can be extracted from stems of various species of Ephedra or it can be chemically synthesized.

Chemical synthesis:1. It is synthesized from benzaldehyde by condensing with nitroethane. The corresponding compound in then reduced. The L-isomer of the reduced compound is then methylated to obtain ephedrine.

2. Benzaldehyde is fermented with glucose using yeast. The fermentation of glucose leads to pyruvic acid formation with is condensed with benzaldehyde. The condensed compound is hydrogenated in presence of methylamine to yield ephedrine.

Ephedrine

Comparison with epinephrineCriterion Ephedrine Epinephrine

Route of Adminis-tration

Effective in oral route Must be given in IV route (except when used as inhaler for asthmatic at-tack)

Duration of action Prolonged Comparatively shorter

Onset of action Slower (thus it is more suitable more chronic asthma and colds) Comparatively rapid

Potency Comparatively less Greater than ephedrineBlood-Brain-Barrier penetration

Greater penetration Penetration is less

CNS activity Greater CNS activity Comparatively less active

VasoconstrictionStronger vasoconstriction Comparatively lower vasoconstric-

tion property.

Tolerance Possible Usually doesn’t occur

Structure      H

C

OH

CH

CH3

HN

CH3

Ephedrine

HC

OH

CH2

HN

CH3

HO

HO

Epinephrine