MSOP1016: The Opioid Analgesics Lecture 4&5 Quiz

Opioid Analgesics

• Opium is a Greek word meaning "juice" or extract of seeds from the poppy Papaver somniferum.
• Morphine is the active principle of opium, which contains over 20 different alkaloids.
• Opioid analgesics are drugs that can relieve pain without causing narcosis (loss of consciousness).

Morphine

• First isolated in 1804 and its correct structure was proposed in 1925.
• Morphine is a T-Shaped molecule with functional groups capable of forming ionic, hydrogen bond, and van der Waals interactions.
• Carbon skeleton is capable of forming van der Waals interactions.
• Mask or remove a functional group to test the analogue for activity and determine the importance of a functional group for activity.

Structure Activity Relationships (SAR)

• Increasing hydrophobicity by adding extra carbons can increase activity.
• Masking polar functional groups can increase activity.
• Correct balance between hydrophobic and polar factors is required for water solubility, fat solubility, oral absorption, and ability to cross the blood-brain barrier.

Heroin

• First synthesised in 1898 and is 2-3 times more potent than morphine.
• Crosses the blood-brain barrier and is metabolised in the liver to morphine.
• Has a stronger analgesic effect than morphine but also has stronger side effects.

Simplification Strategies

• Removing non-essential functional groups, excess rings, and excess asymmetric centres can give rise to simpler analogues with increased activity.
• Simplification can lead to easier and cheaper synthesis, but may also increase or decrease side effects.

Morphinans

• Removing the oxygen bridge (ring D) and the hydroxyl and alkene functional groups gives a series of tetracyclic compounds called the morphinans.
• N-methylmorphinan is the simplest of the morphinans and has 20% the activity of morphine.

Benzomorphans

• Removing both rings C and D gives rise to the benzomorphans, which retain analgesic activity.
• The simplest, metazocine, has the same analgesic activity as morphine.
• Replacing the N-methyl group of metazocine with a phenyl group gives phenazocine, which is 4 times more active than morphine.

Pethidine

• Removing ring B gives pethidine, which is useful for child labour and has less severe emetic and constipation effects.
• Generates morphine in the brain, but has less severe withdrawal symptoms.

Buprenorphine

• Has a minimal euphoric effect and less severe withdrawal symptoms.
• Used as a substitute for morphine or heroin to treat addicts.
• Has a flexible molecule with a different binding mode from morphine.
• R form has 2x the activity of morphine, and S form is inactive.

Opioid Receptors

• Morphine has 3 receptors: Mu (µ), Kappa (κ), and Delta (δ).
• Mu is the main receptor for analgesic and side effects.
• Kappa has a weak analgesic effect, and Delta has a weak analgesic effect.
• Drug selectivity for peptide and opioid drugs for receptor subtypes is important.

Aims of Opioid Drug Design

• To maintain activity while lowering side effects.
• To increase oral activity.
• To design agonists with a low risk of addiction and dependence.