Natural Products

Dr Suzanne Fergus s.fergus@herts.ac.uk

Morphine
Excellent Analgesic Serious Side Effects: Respiratory depression Addiction Nausea Drowsiness Constipation Euphoria
Source: Opium Poppy 1803 Isolated main alkaloid

Administered by injection (subcutaneous or intramuscular) 10mg every 4 hours What can you say about solubility of morphine?

SIDE EFFECTS??

Blood Brain Barrier

The blood-brain barrier (BBB) is formed by the brain capillary 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 porous capillaries perfusing all peripheral tissues but is excluded from entry into the brain or spinal cord by the BBB.

Morphine

Opioid Receptor Interactions

Ionic Bond interaction with protonated 3 amine Hydrogen Bond with phenol Van der Waals with aromatic ring

Opioid Receptor Interactions

Structure Activity Relationships

Mask or remove a functional group Test the analogue for activity Determines the importance or otherwise of a functional group for activity

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 produce morphine

Removing the oxide bridge (and hydrogenating double bond, removing one alcohol) produces levorphanol, which has enhanced analgesic properties over morphine.
HO
4 2 3 1 11 12 13 15 14 9 10 16 4 12 13 15 14 9

HO

2 3 1 11 10 16

O
5 6

H
8

N CH3

5 6

H
8

N CH3

HO

Levorphanol

Levorphanol is used to treat severe pain and has several brand names.

Levorphanol
Removing the oxide bridge (and hydrogenating double bond, removing one alcohol) produces levorphanol, which has enhanced analgesic properties over morphine

Mirror image has antitussive properties, but no analgesic properties

2 1 11 16 10 9 15 14 12 13 3 4

OH

HO
4

2 3 1 11 12 13 15 14 9 10 16

N H3C

H H
8

5 6

5 6

H
8

N CH3

dextrorphan Antitussive only

Levorphanol analgesic + antitussive

Mirror
Dextromethorphan (DM or DXM) is an antitussive drug that is found in many over-the-counter cold and cough preparations, usually in the form of dextromethorphan hydrobromide.

Pethidine

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

 Fentanyl is most lipid-soluble and morphine 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.

 Elimination half-lives: 2-4 hours for morphine 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.

Heroin (Diamorphine)

2 x more active than morphine

How do we explain this ?

4 x more active than morphine

What structural elements are necessary for activity ?

Aromatic Ring Spacer
HO
4 2 3 1 11 12 13 15 14 9 10 16

O
5 6

H
8

N CH3

R1

R2

N R3 CH3

HO

Quaternary Carbon Center

Basic Nitrogen

Methadone

Orally active Side Effects less severe (sedation, Euphoria & withdrawal symptoms

10,000 more potent !!

Etorphine can cross BBB 300x more easily than morphine as is hydrophobic and has 20x better receptor binding

The impact of natural products on the well being of mankind has been enormous and their study continues to influence research in the fields of chemistry, biology and pharmacy. (J. Med. Chem., 2008) Critically discuss using relevant examples.