MEDICINAL CHEMISTRYIII
Lecture 4
Sat. 19/ 5/ 1432H
Analgesics
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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
Centrally Acting Analgesic
(Narcotic analgesic)
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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
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Isoquinoline ring system
e.g. Papaverine
Centrally Acting Analgesic
Opioid agonists
a. Morphine and morphinan derivatives
e.g. Morphine, Codeine …………
I.
b. Piperidine derivatives
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Mepiridine and congeners
Methadone and congeners
Other structures e.g. Tramadol
II Mixed Opioid Agonist-Antagonist and Partial
Agonists
e.g. Nalorphine
II Opioid Antagonists
e.g. Levallorphan
III Nonopioid compounds
e.g. Nefopam
Opioid Agonists
Morphine
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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.
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Other effects:
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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……………..
Structure activity relationships:
Stereochemistry:
Natural morphine is levo (-), the dextro
isomeris has been synthesized and it is
devoid of analgesic and other opioid
activities.
1. Alkylation of OH at C-3
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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
Methylation
(CH3I)
Codiene
Morphine
O-demethylation (HI)
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Ethylation
Dionine (ethyl morphine)
7,8-didehydro-4,5-epoxy-3-ethoxy-17methylmorphinan-6-ol
Dionine is used in ophthalmology as analgesic, especially
in glucoma
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Alkylation with
morphoine ethyl
chloride
Pholcodine
CH3
N
O
O
O
N
7,8-didehydro-4,5-epoxy-3-O- (2-morphoinoethyl)-17methylmorphinan-6-ol
Pholcodine used as antitussive
OH
2. Acetylation: at C-3 & C-6
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(Diamorphine, Heroin) (diacetyl morphine)
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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.
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7,8-didehydro-4,5-epoxy-3,6-diacetyloxy-17-methylmorphinan.
7,8-double bond
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Reduction of 7,8 double bond ……………….dihydromorphine
………………..dihydrocodiene
4,5-epoxy-17-methylmorphinan
3,6-diol
is more active than morphine
4,5-epoxy-3-methoxy-17-methylmorphinan-6-ol
antitussive, analgesic
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If the reduction is accompanied by oxidation of OH at C-6 to
ketone…………………….. activity
toxicity
Hydromorphone
4,5-epoxy-3-hydroxy-17methylmorphinan-6-one
Hydrocodone
4,5-epoxy-3-methoxy-17methylmorphinan-6-one