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Natural Products

Dr Suzanne Fergus

s.fergus@herts.ac.uk

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MorphineExcellent Analgesic

Serious Side Effects:Respiratory depression

Addiction

Nausea

Drowsiness

Constipation

Euphoria

Source:

Opium Poppy

1803 Isolated main alkaloid

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Administered by

injection

(subcutaneous orintramuscular)

10mg every 4 hours

What can you say

about solubility of

morphine?

SIDE EFFECTS??

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Blood Brain Barrier

The blood-brain barrier (BBB) is formed by the braincapillary endothelium and excludes from the brain 100%

of large-molecule neurotherapeutics and more than 98%

of all small-molecule drugs

Example: Histamine readily crosses the porouscapillaries perfusing all peripheral tissues but is excluded

from entry into the brain or spinal cord by the BBB.

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Morphine

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Opioid Receptor Interactions

Ionic Bond interaction with protonated 3

amine

Hydrogen Bond with phenol

Van der Waals with aromatic ring

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Opioid Receptor Interactions

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Structure Activity Relationships

Mask or remove a functional group

Test the analogue for activity

Determines the importance or otherwise of afunctional group for activity

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Codeine

Only 0.2-0.7% codeine

available in opium

Methylation of morphine

Non-addictive

Codeine 20% active (injected

peripherally) 0.1% active (injected into brain)

Prodrug-partly demethylated in liver to producemorphine

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Removing the oxide bridge (and hydrogenating

double bond, removing one alcohol) produces

levorphanol, which has enhanced analgesicproperties over morphine.

O

HO

H

NH

CH3

HO1

23

4

5

6

7

8

9

1011

12

1314

15 16

H

NH

CH3

HO1

23

4

5

6

7

8

9

10

11

12

1314

15 16

Levorphanol

Levorphanol is used to treat severe pain and has several

brand names.

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Levorphanol

Removing the oxide bridge (and hydrogenating double

bond, removing one alcohol) produces levorphanol,which has enhanced analgesic properties over morphine

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Mirror image has antitussive properties,

but no analgesic properties

H

NH

CH3

HO1

2

3

4

5

6

7

8

9

10

11

12

1314

15 16

Levorphanol

H

NH

H3C

OH1

2

3

4

5

6

7

8

9

10

11

12

1314

1516

dextrorphan

Mirror

analgesic + antitussiveAntitussive only

Dextromethorphan (DM orDXM) is an antitussive drug that

is found in many over-the-counter cold and cough

preparations, usually in the form of dextromethorphanhydrobromide.

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Pethidine

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Fentanyl (A Piperidine)

100 times more active than morphine!

Most potent agonist for opioid

receptor

Can efficiently cross the BBB

Lacks phenolic group and is

therefore LIPOPHILIC

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Fentanyl is most lipid-soluble andmorphine is the least lipid-soluble.

The octanol-water partition coefficient for

morphine is 6 and 9550 for fentanyl.

This difference in lipid solubility has

profound effects on how we can use these

2 drugs in clinical practice.

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Elimination half-lives: 2-4 hours formorphine and 3-7 hours for fentanyl.

Morphine lasts longer because once it

enters the central nervous system it has a

difficult time exiting the cellular lipid barrier

(blood-brain barrier). It is this retention in

the central nervous system that makes

morphine longer-acting than fentanyl.

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Heroin (Diamorphine)

2 x more active

than morphine 4 x more active

than morphineHow do we explain

this ?

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What structural elements are

necessary for activity ?

O

HO

H

NH

CH3

HO1

23

4

5

6

7

8

9

10

11

12

1314

15 16

R3R1

N

CH3

Basic NitrogenQuaternary Carbon Center

Spacer

R2

Aromatic Ring

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Methadone

Orally active

Side Effects less severe (sedation,

Euphoria & withdrawal symptoms

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10,000 more potent !!

Etorphine can cross BBB

300x more easily than

morphine as ishydrophobic and has 20x

better receptor binding

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The impact of natural products on the well

being of mankind has been enormous andtheir study continues to influence research

in the fields of chemistry, biology and

pharmacy. (J. Med. Chem., 2008)

Critically discuss using relevant examples.