Morphine alkaloids

1. Morphine alkaloids as lead
drug molecules
PRESENTED BY
YEHTESHAM KHURSHID
M.PHARM (PHARMA. CHEMISTRY)
FIRST SEM.
SPER, JAMIA HAMDARD

2. What is Lead compound ?
 A Lead compound is generally defined as a new chemical entity that could be
potentially developed into a new drug by optimizing its beneficial effects and
minimizing its side effects.
 Lead compounds are typically used as starting points in the drug design to
give new drug entity.
 Drug design strategies can be used to improve the compounds
pharmacological properties.

4. Introduction
 Morphine was first isolated in 18th century by German pharmacist Friedrich
Serturner from the opium poppy (Papaver somniferum)
 In opium, it is present in the quantity of 10-23% along with other substances of
fats, resins, proteins and so on.
 Codeine, Thebaine and morphine are closely related alkaloids- opium alkaloids.
 Used as analgesic agent.
 Colourless , prismatic with a bitter taste.
 Soluble in alcohol and alkali solution.
 Due to the presence of phenanthrene nucleus these are also known as
phenanthrene alkaloids

5. Source
 Opium or gum opium poppy capsules.
 It is obtained from dried latex of unripe capsules of papaverine species (by vertical
incisions of 0.1 to 0.5 mm depth ).
Papaverine somniferum
P. bractatum
P. orientale
P. rhoeaes
Commercial varieties –
Turkish opium
Indian opium
Chinese opium
Russian opium

6. Morphine Nucleus
Structure

7. Morphine is belonging to class of phenanthrene.
Its main skeleton is of phenanthrene and contain many
functional groups, like ;
 Free Phenolic group
 Alcohol at sixth position
 Aromatic Ring
 The double bond at 7-8
 The N-methyl group
 The ether bridge

8. Structural activity relationship
1) Modification on alicyclic ring
 The alcoholic hydroxyl group at C-6 when methylated, esterified, oxydized,
removed or replaced by halogen analgesic activity as well as toxicity of the
compound increased.
 The reduction of C-6 keto group to C-6 beta hydroxyl in oxymorphine gives
Nalbuphine, it shows antagonistic action of mu receptors.

9.  The 14 beta hydroxyl group generally enhances mu agonistic
properties and decreases antitussive activity. However, activity
varies with the overall substitution on the structure.
 The saturation of the double bond at C-7 position gives more
potent compound. Example, Dihydromorphine and
Dihydrocodeine.

10.  The saturation of the double bond at C-7 position gives more
potent compounds. Example, Dihydromorphine and
Dihydrocodeine.
 Bridging of C-6 and C-14 through ethylene linkage gives
potent derivatives.
22)Modification on phenyl ring ring
 An aromatic phenyl ring is essential for activity.
 Modification on phenolic hydroxyl group decreases the
activity.
 Any other substitution on phenyl ring diminishes activity.

11. 3)Modification of 3° Nitrogen
• A tertiary amine is usually necessary for good opioid activity.
• The size of the N substitution can dictate the compounds potency
and its agonists and its reverse antagonistic properties.
• The N-methyl substitution is having good agonistic property, when
increased the size of the substitution by 3-5 carbons results in
antagonistic activity. Still larger substituents on N returns
agonistic property of opioids. For example – N-phenyl ethyl
substitution is 10 times more potent than N-methyl groups.
• N-allyl and N-cyclo alkyl group leads to narcotic antagonistic
property.

12. 4)Modification on epoxide Bridge
 Removal of 3,4 epoxide bridge in morphine Structure
results in the compounds that is refered to as
morphinans.

13.  The morphinans are prepared synthetically. As the
synthetic procedure yielded compound is a racemic
mixture, only levo isomer possesses opioid activity
while the dextro isomer has useful antitussive activity.
For example – Levorphanol and Butorphanol.
• Levorphanol is a more potent analgesic than
morphine.
Levorphanol Butorphanol

14. Reference
1.Wilson and Gisvold's Textbook of Organic Medicinal and Pharmaceutical Chemistry
2.Sriram. D, Yogeeswari. P. (2008) Medicinal chemistry
3.Graham l. Patrick, An Introduction to Medicinal Chemistry, 1995, pgs 250-255
4. Kumar. S, Talapatra, Bani Talapatra, Chemistry of Plant Natural Products: Stereochemistry,
Conformation, Synthesis, Biology, and Medicine. 2015 ,vol 1.

15. Thank You