1. MEDICINAL CHEMISTRY-III
Lecture 4
Sat. 19/ 5/ 1432H

2. Analgesics The analgesics may be divided into two main classes:
a) Opium and its alkaloids [morphine & related compounds] ……..Narcotics Analgesics or Opiate Drugs
b) Non-Opiate Drugs [Aspirin & Phenacetin] ……… ……..Analgesic Antipyretics

3. Centrally Acting Analgesic (Narcotic analgesic)
The term centrally acting analgesic is used for compounds which inhibit the pain reaction within the central nervous system.
Opium contains more than 25 alkaloids. There are two types of ring systems found in opium alkaloids
Phenatheren ring system
e.g. Morphine, Codeine, Thebaine

4. Isoquinoline ring system
e.g. Papaverine

5. Centrally Acting Analgesic
Opioid agonists
a. Morphine and morphinan derivatives
e.g. Morphine, Codeine …………
b. Piperidine derivatives
Mepiridine and congeners
Methadone and congeners
Other structures e.g. Tramadol

6. II Mixed Opioid Agonist-Antagonist and Partial Agonists
e.g. Nalorphine
II Opioid Antagonists
e.g. Levallorphan
III Nonopioid compounds
e.g. Nefopam

7. Opioid Agonists Morphine
7,8-didehydro-4,5-epoxy-17-methylmorphinan-3,6-diol
It is the principle alkaloid obtained from the dried latex (opium) from the unripe fruit of poppy (papaver somniferum)
Morphine is one of the most effective pain killers in medicine. It is used in treating dull constant pain.

8. Other effects: Respiratory depression Constipation
Tolerance and physical dependence
Euphoria
Nausea and vomiting
Dull
Pupil constriction
Biliary colic
Flushing and warming
1, 3, 5, are the most dangerous side effects. Withdrawal symptoms are also dangerous, they include anorexia, pupil dilatation, chills, excessive sweating, cramps, muscle spasms, irritability, tremors etc……………..

9. Structure activity relationships:-
Stereochemistry:
Natural morphine is levo (-), the dextro isomeris has been synthesized and it is devoid of analgesic and other opioid activities.

10. 1. Alkylation of OH at C-3 Methylation Codeine
Codeine has less analgesic activity & used mainly as antitussive drug.
7,8-didehydro-4,5-epoxy-3-methoxy-17-methylmorphinan-6-ol
Codeine …………… Prodrug…………..metabolized ……………Morphine

11. Dionine (ethyl morphine)
Ethylation
Dionine (ethyl morphine)
7,8-didehydro-4,5-epoxy-3-ethoxy-17-methylmorphinan-6-ol
Dionine is used in ophthalmology as analgesic, especially in glucoma

12. Alkylation with morphoine ethyl chloride
Pholcodine
7,8-didehydro-4,5-epoxy-3-O- (2-morphoinoethyl)-17-
methylmorphinan-6-ol
Pholcodine used as antitussive

13. 2. Acetylation: at C-3 & C-6 (Diamorphine, Heroin) (diacetyl morphine)
Characters:
- more potent analgesic than morphine
due to its high lipid solubility.
- more addictive.
- weaker antitussive.
- metabolism ………….. 6-acetyl morphine which is more active than morphine.
…………… diacetylation of acetyl group at C-3 & C-6 giving morphine.
7,8-didehydro-4,5-epoxy-3,6-diacetyloxy-17-methylmorphinan.

14. 7,8-double bond Reduction of 7,8 double bond ……………….dihydromorphine
………………..dihydrocodiene
4,5-epoxy-17-methylmorphinan ,5-epoxy-3-methoxy-17-methyl-
3,6-diol morphinan-6-ol
is more active than morphine antitussive, analgesic

15. If the reduction is accompanied by oxidation of OH at C-6 to ketone…………………….. activity toxicity
Hydromorphone Hydrocodone
4,5-epoxy-3-hydroxy ,5-epoxy-3-methoxy-17-
methylmorphinan-6-one methylmorphinan-6-one