Opioid Agonists and Antagonists

Opioid Agonists and Antagonists

• The opioid agonists and antagonists will be classified based on the structural classification.

Structural Classification of Opioid Agonists

• There are eight classifications:

  1. 4,5-epoxymorphinans

  2. Morphinans

  3. Benzomorphans

  4. 4-phenylpiperidines

  5. 4-anilidopyridines

  6. Diphenylheptanes

  7. Miscellaneous opioid agonists

  8. Mixed agonist or antagonist

Four-Five Epoxymorphinans

• These are the basic opioids. Structure-activity relationship will be discussed.

  • Examples: Morphine, Codeine, Heroin, Oxycodone, Hydrocodone, Oxymorphone, Hydromorphone

  • Key structural features:

  • Aromatic ring (typically phenyl group) crucial for receptor binding.

  • Tertiary amine nitrogen: essential for activity; usually protonated at physiological pH, allowing ionic interactions with the receptor.

  • Quaternary carbon: contributes to the molecule's three-dimensional shape and interaction with the receptor.

  • Hydroxyl groups: presence and position affect potency and receptor selectivity. For instance, morphine has two hydroxyl groups.

  • carbon number 17 are bulky, specifically cyclopentane and cyclopropane

  • morphine has 5 rings

• Morphine

  • prototype u-receptor agonist

  • contains 5 chiral centers and 16 optical isomers

  • isolated by: Serturner

  • isolated from: opium poppy

    Natural opium derivatives:

  • morphine

  • codeine

  • thebaine

  • papaverine

  • noscapine

MORPHINE

• standard, why? because it is a drug to which all other u-agonists are compared

• since morphine is a standard, if there is a new drug it will be compared to morphine, it is called as equivalent analgesic effect: oral dose must be 3x the IV dose to account for the morphine lost to first-pass metabolism

• oral dose: 30 mg, parenteral dose: 10 mg

Codeine oral dose:200 mg, Parenteral dose: 130 mg. This demonstrates that codeine is less potent as an analgesic than morphine, as it requires a higher oral dose to achieve comparable analgesic effects.

• Metabolism of morphine is extensively metabolized via phase ii conjugation

  3 metabolites
  - morphine-3-glucuronide

  - morphine-6-glucuronide

  - N-demethylated metabolite

Clinical use of Morphine: introduces in the WHO stepladder when pain is severe, and no relief is obtained from NSAIDS or a combi of NSAIDs and a less potent opioid.

MORPHINE AND OTHER NARCOTIC ANALGESIC SHOULD ONLY BE USE FOR SEVERE PAIN

PHARMACOKINETICS

• monoacidic base

• readily forms water-soluble salts w most acids

• sulfate salt: PO, IV, suppository

• usual dose (adults): 2.5 to 5mg q4h

• PO: IR( IMMEDIATE RELEASE) q4h, SR(SUSTAINED RELEASE) q12h

CODEINE

• naturally occurs in opium

• prepared from Morphine: methylation

• not used as an analgesic it is primarily used as antitussive agent or cough suppressant

• Cohcrane evidence based rev.: it is no more effective than placebo for acute cough in children or adults.

• decreased analgesic potency vs. morphine: lower addiction potential

• AE: respi. depression, miosis, constipation, nausea, itching, dry mouth, and drowsiness
  but what stands out in AE of opioid analgesics: constipation, miosis, dry mouth n respi depression (if there is an opioid poisoning or intoxication)
  
  SAR; difference bn codeine n morphine

• C is in carbon no. 3 bc of methylation= methoxy
  METABOLISM
  

  

  
  HEROIN

HISTORY

• 1st commercially synthesized in 18998 by Bayer (Germany)

• purpose: alternate analgesic to morphine

• structure: 3,6-diacetylated form of Morphine

  • carbon 3 n 6, may acetylation

• researchers believed that it would be an effective analgesic with no addictive properties.

“HEROIN” why is it called

• it made the test sub., including some chemists, feel heroic

• however they didn’t realize that heroin would became part of the opioid epidemic crisis in the U.S
  

  

(euphoric rush- kaya addictive lalo na pag IV)
metabolized to: 3-acetylmorphine, 6-acetlymorphine (si 6 is 2 to 3x more potent than morphine, so even heroin is already metabolized, it is also activated to it’s active metabolite which is si 6 chuchu)

brand name: Dilaudid®

• synthetic derivative of morphine

• catalytic hydrogenation and dehydrogenation of morphine

• Structure

• oxidation of 6-OH: decrease of potency

disappearance of double bond= dehydrogenation

• reducing 7-8 double bond: increase flexibility of hydromorphone bc nagkaroon ng enhanced binding at the mew receptor, which makes hydromorphone 5x potent as morphine

• available as IR tablet, liquid, or suppository

STRUCTURE

• 3-methoxy version of Hydromorphone - better brain penetration

• loss of 3-OH group

• 4-5x less potent than Hydromorphone

• 7-8-dihydro-6-keto C ring

- no pure hydrocodone

- products anti-tussive agent

Combination Products

• Hydrocodone + Homatropine(anticholinergic agents): Tussionex® (antitussive agent)

• Hydrocodone + paracetamol: Vicodin®, Lortab

• Hydrocodone + Aspirin: Lortab ASA

Structure-Activity Relationship (SAR)

• Modification Effects:

  • N-substitution:

  • Small alkyl groups (e.g., methyl) generally retain agonist activity.

  • Larger groups can lead to mixed agonist-antagonist or pure antagonist activity (e.g., naloxone).

  • 3-OH substitution:

  • Methylation (e.g., codeine) reduces potency compared to morphine due to decreased receptor binding affinity.

  • Acetylation at both 3- and 6-OH positions (e.g., heroin) increases lipophilicity, leading to faster entry into the brain and a more rapid onset of action.

  • 6-OH substitution:

  • Oxidation to a ketone (e.g., oxymorphone, naloxone) can increase potency or alter activity profile.

  • Saturation of 7,8-double bond:

  • Saturation generally increases receptor binding affinity and analgesic potency (e.g., hydromorphone).

  • Removal of the N-methyl group:

  • Results in a significant decrease in analgesic activity.

  • C14 substitution:

  • The introduction of a hydroxyl group at the C14 position (e.g., oxymorphone) enhances analgesic activity.