6. Opioid Med Chem

Mechanism of action

Opioid effects

• Analgesia

• Euphoria

• Respiratory depression

• Emetic effects

• Constipation

• Tolerance/dependence

Opioid SAR

Exam question:
What is the difference between the morphine and naloxone molecule?

What is the structural difference between opioid agonists and antagonists?

• In naloxone, the methyl group is replaced with an allylic group on the amino group, changing it from an agonist to an antagonist

• Hydroxyl group changed to a ketone = higher affinity for the receptor, a more potent molecule

• OH group added and no double bond changes from having cough suppression to something that is not going to have that activity

Opioid Agonists

Agonists activate the μ-opioid receptor and produce effects such as:

• Analgesia

• Euphoria

• Respiratory depression

• Sedation

Examples:

• Morphine

• Hydromorphone

• Oxycodone

Structural Feature

Agonists typically have a small N-substituent, such as:

• N-methyl (−CH₃)

Example:

Morphine contains an N-methyl group, making it a strong agonist.

Opioid Antagonists

Antagonists bind to the receptor but do not activate it.

They block the effects of opioids.

Examples:

• Naloxone

• Naltrexone

Structural Feature

Antagonists usually have a larger N-substituent, such as:

• Allyl group (−CH₂CH=CH₂)

• Cyclopropylmethyl group

These larger groups change how the molecule interacts with the receptor and prevent activation.

Examples:

• Naloxone = N-allyl derivative of oxymorphone

• Naltrexone = N-cyclopropylmethyl derivative

Exam question: What is the difference between morphine and heroin; why does heroin produce more intense euphoria than morphine

• Lipophilicity

  • heroin enhanced lipophilicity allows for higher BBB penetration, higher concentration in CNS

  • then converted to morphine in that space

• Heroin is a pro-drug for morphine

Heroin produces more intense euphoria than morphine because it is more lipid-soluble (more fat-soluble), so it crosses the blood-brain barrier much faster.

Once heroin enters the brain, it is rapidly converted into morphine, leading to a faster and higher concentration of morphine in the brain, which causes a stronger "rush" and more intense euphoria.

Simple memory:

• Morphine: enters the brain slower → less intense euphoria

• Heroin: enters the brain faster → more intense euphoria and "rush"

The reason heroin enters the brain faster is that its two hydroxyl (OH) groups have been acetylated, making it more lipophilic.

What is the structural difference between opioids that are cough suppressants and those that are not?

• Cough suppressing opioids typically have the 3-phenolic OH methylated to a 3-methoxy group (OCH₃), as seen in codeine. This reduces analgesic activity while maintaining antitussive activity.

• Memory Trick

  • 3-OH = stronger pain relief (morphine)

  • 3-OCH₃ = better cough suppressant (codeine)

Opioid metabolism

• metabolism occurs primarily in liver

• metabolites excretes in urine - renal function important for effectively clearing metabolites and the drug molecule

• codeine has analgesic activity, but it is weaker than morphine

• CYP2D6 necessary for codeine conversion to morphine

Other opioid agents (4)

Opioid disjunctive pharmacophore ID

• Describe the general pharmacophore of natural product-based opioids

1. Start with morphine molecule:

   1. Multiple fused rings, bridge structure, tertiary amine (nitrogen), oxygen-containing group that can hydrogen bind

   2. Because of these rings, morphine is rigid

2. Morphine --> Meperidine (Demerol)

   1. Remove some of morphine's ring systems created Meperidine

   2. Even with these changes, Demerol still relieves pain and binds to opioid receptors

3. Morphine --> Methadone

   1. Remove more structural complexity forming methadone, it looks even less like morphine but still act as an opioid

 

If morphine, meperidine, and methadone all activate opioid receptors despite looking different, they must share common essential features:

• A basic nitrogen (Amine)

  • Positive charge interacts with negative charged site on the opioid receptor

• An aromatic ring (usually a phenyl ring)

  • Provides hydrophobic interactions with the receptor

• Oxygen containing group to participate in hydrogen binding

  • Phenol OH

  • Ether Oxygen

  • Carbonyl oxygen

• Proper distance between the aromatic ring and nitrogen

  • The receptor cares less about the exact rings and more about:

    • Where the aromatic ring is

    • Where the nitrogen is

    • How far a part they are

  • The molecule can look completely different as long as these features are positioned correctly in 3D space

Why did removing the rings still work?

• The rings mainly:

  • Hold the pharmacophore in a specific shape

  • Control flexibility

  • Affect potency and pharmacokinetics

• But the rings themselves are not always required for receptor activation

• Chemists learned that receptor recognizes the pharmacophore, not necessarily the entire morphine skeleton

Opioid Pharmacophore Similar to Antiarrhithmics

Fentanyl Discovery

Opioid DDIs

Dosage forms

• Morphones are often preferred rectally because they undergo more extensive first-pass metabolism and have lower oral bioavailability, so rectal administration can increase systemic exposure. In contrast, -codones already have good oral bioavailability, making the rectal route less advantageous.

Are there potential clinical uses with use of opioids in patients polymorphic in enzymes responsible for metabolizing opioids?

• Yes. Genetic polymorphisms in opioid-metabolizing enzymes (especially CYP2D6) can be used to individualize opioid therapy. Poor metabolizers may not obtain analgesia from prodrugs like codeine, while ultrarapid metabolizers may experience toxicity. Therefore, genotype-guided opioid selection can improve efficacy and safety.

CYP2D6 Polymorphism

• Poor Metabolizers (PMs)

• They have little or no CYP2D6 activity.

  • Codeine is poorly converted to morphine.

  • May get little or no pain relief.

  • Similar issue with Tramadol.

  • Clinical use: Avoid codeine/tramadol and choose opioids that do not require CYP2D6 activation (e.g., morphine, hydromorphone).

• Ultrarapid Metabolizers (UMs)

  • They have very high CYP2D6 activity.

  • Convert codeine to morphine very quickly.

• Can develop excessive opioid effects:

  • Sedation

  • Respiratory depression

  • Toxicity

Clinical use: Avoid codeine/tramadol because of overdose risk.