Morhine and its simplification and addition

1. Presented by:
Mr. Afroj Shaikh
M.Pharm MNP

2.  Biological source: Dried latex extruded from
the seedpod of Papaver somniferum
(Papaveraceae)
 First active principle isolated from plant.
 Segnin 1804.
 Geographical source:- Mediterranean region
 Cultivation.
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3. Powdered opium
(shake with CaCl2 & Filter)
Add 10% NaOH solution
Filtrate
(Mor. Cod. Narceine) CHCl3
Precipitate
CHCl3 layer
Codeine
Aqueous layer
Acidify then Slightly alkaline NH4
Aqueous Sol.
Precipitate
Narceine
Morphine
Thebeine
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4. D(-) Morphine
B C Ring fusion is Cis
C D fusion is Trans
Chiral centre
Pentacyclic ring structure A,B,C,D,E.
OH functional group C3 C6
C4 C5 ether linkage – epoxy
C7 C8 unsaturation
tertiary amine function more basic.
Insoluble in Water, Chloroform, ether.
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5.  Limited Oral bioavailability
 Lipophilic but less
 Half life- 2-3 hrs.
 Elimination:- urine by glucuronide.
 Metabolism 3 and 6 O glucuronidation & O
methylation to Codeine.
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6.  Morphine exerts its major effects by interacting
with opioid receptors in the CNS
 Opioids activate 7- transmembrane GPCRs
located pre-synaptically and post-synaptically
along pain transmission pathways
 It has agonistic action at the μ, k and δ
 μ receptor:- Respiratory depression & analgesia
 k receptor:- Sedation
 δ receptor:- urinary retention and constipation
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7.  Based upon
 Phenolic OH group C3
&6 hydroxy
 7-8 unsaturation
 N methyl group
 Ether linkage
 Aromatic ring
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8.  Essential for the binding at Kappa or mu
receptor
 Changing to H or O CH3 decreases the activity
OH Morphine
H Activity deceases
O CH3 Codeine
Activity decreases
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9. > 5 C (In chain or ring ) Agonist
3-5 C with = /
Small cyclic / Aromatic
ring
Antagonist
Naloxone/Naltrexone
Aryl alkyl Increases 10 fold
 Interact hydrophobically with mu receptor
 Size of substitution on N determines the
potency and activity (Agonistic or
Antagonistic)
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10. Removal of OH reduces activity
Removal decreases
activity
Oxidation, acetylation, reduction 7=8 Increases activity
N-CH2=CH2-Ph increases
activity
N-CH2-CH2=CH2 creates
Antagonists
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11. Morphine
Codeine Heroin
Thebaine
C.R. Alder wright 1874
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12. Oxymorphone
Hydrocodone
Oxycodone
Hydromorphone 12

13.  Additional approach
 Addition of the extra ring in the morphine structure
gives active compound
 Simplification approach
 Deletion of the ring from morphine structure gives
active compound.
 Simplification approach is used for synthesis of a
new classes of compounds.
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14.  Addition of extra ring
in Morphine gives
Oripavines,
Naltrindole etc.
 Potency is comparable
to morphine but not
used clinically
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15.  Removing ring D
 Morphinans
 Useful analgesic
activity
 Oxygen bridge not
essential
 Eg. Dextrallorphan
 It acts as a σ1 receptor
agonist
 It has no significant
affinity for σ2, mu
opioid, or δ- opioid
receptor or serotonin
or NE.
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16.  Removing ring C & D from morphine nucleus
 Benzomorphans / Benzazocine
 It retains analgesic activity
 Eg:- Alazocine, Anazocine, Ketazocine,
Metazocine etc.
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17.  Removing ring B, C & D from morphine
nucleus.
 4- Phenyl pepiridine/Mepiridine series.
 It was discovered by chance in 1940 when
chemists were studying analogues of cocaine
for anti spasmodic activity.
 Eg:-Mepiridine, Bemidone,Properidine etc.
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18.  Removing ring B, C, D & E from morphine
nucleus. Methadone series.
 Retention Tertiary amine and aromatic function
It is an opioid used to
treat pain & as
maintenance therapy or to
help with detoxification in
people with opioid
dependence.
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