Faculty Of Pharmacy ASUDepartment of Pharmaceutical

Chemistry4th year - Section 6

Opioid Analgesics

Opioid drugs, typified by morphine, produce their pharmacological actions, including analgesia, by acting on receptors located on neuronal cell membranes.

Morphine (1804):Named after the Greek God, Morpheus (God of dreams)Good for treating dull, constant pain rather than sharp, periodic pain.Side effects: -Excitation, Euphoria

-Nausea, Pupil constriction-Constipation,-Tolerance and Dependence,-Depression of breathing.

Why it gives feelings of Euphoria and causes addiction?There are different types of Opioid Receptors, Its action depends on the type of receptor morphine binds to…

Receptor type

Location Effects

μ Brain, spinal cord

Analgesia, Respiratory depression, euphoria, addiction, ALL pain messages blocked

κ Brain, spinal cord

Analgesia, sedation, all non-thermal pain messages blocked

δ Brain Analgesia, dependence

Now, Let’s see together the effect of masking or removing functional groups on activity…1- The Phenol Moiety:Masking the phenol group resulted in decreased activity, thus it is crucial for activity.R=H Morphine

R=Me Codeine

Codeine 20% active (injected peripherally)0.1% active (injected into brain)

NMe

O

RO

HOHH

2- The 6-alcohol:

•Activity increases due to reduced polarity•Compounds cross the blood brain barrier more easily•6-OH is not important for binding

NMeO

HO

HO

NMeO

HO

O

NMeO

HO

R=Ac 6-Acetylmorphine

Increased activity (4x)

•Acetyl masks a polar alcohol group making it easier to cross BBB•Phenol group is free and molecule can bind immediately•Dependence is very high •6-Acetylmorphine is banned in many countries

NMeO

HO

ROHH

3- The Double Bond at 7,8:

Dihydromorphine

Increased activity

The alkene group is not important to binding.

NMeO

HO

HOHH

4- The 3o Amine:

No activity

Nitrogen is essential to binding.

CHMeO

HO

HOHH

NR= NH NormorphineReduced activity (25%)

NR= N+Me2

No activity

•Normorphine is more polar and crosses the BBB slowly•Note: R affects whether the analogue is an agonist (axial and reaching to agonist site) or an antagonist (equatorial and reaching to antagonist site), rigidification could be applied to stabilize such conformations.•Optimum distance between 3o amine and phenyl ring is essential for activity.

NR

O

HO

HOH H

Important Binding Interactions:HBD or HBA

Ionic (N is protonated)

van der Waals

NMeO

HO

HOH H

Morphine analogs available as drugs:1- Codeine (1832):How it’s related: Methyl ether of morphine.Activity: 20% that of morphine.Treats: Moderate pain, Coughs, diarrhea.

2- Heroin (1874):How it’s related: 3,6-diacetyl ester of morphine.Activity: 2x that of morphine as it is easier to cross BBB.Treats: Pain in terminally ill patients.Side effects: Euphoria, addiction, tolerance.

5- Methadone(1937):How its related: Rings B,C,D,E opened.Activity: Less than Morphine.Used to: Treat addiction.Advantages: Can be given orally, Less side effects.

3- Levorphanol (1948):How it’s related: Ether bridge removed.Activity: 5x that of morphine.Advantage: It can be taken orally, Lasts longer, Easier to synthesize.Side effects: High toxicity, comparable dependence.

4- Fentanyl (1960):How it’s related: Rings B,C,D removed.Activity: 100x that of morphine.Advantages: Cross BBB efficiently, Really easy to make, Rapid onset, short duration, Can be administered any route (IV, oral, transdermal, buccal).Used for: Anesthesia and Chronic pain managementSide effects: Sudden respiratory depression, More addictive than heroin, Less euphoria, more sedation.

8- Dipipanone (1970):How it’s related: Rings B,C,D opened.Activity: Similar to morphine.Used for:  Patients allergic to morphine.Side effects: Sudden respiratory depression, risk of abuse.

6- Sufentanil (1974):How it’s related: Rings B,C,D removed.Activity: 500x that of morphine Advantages: Strongest Pain killer available for humans.Used for: in surgery and post-operative pain management for patients that are heavily Opioid tolerant because of long term opiate use.Side effects: Sudden respiratory depression, anaphylaxis in rare cases.

7-Tapentadol (2008):How it’s related: Rings B,C,D removed.Activity: Weak μ agonist and inhibit the reuptake of norepinephrine (similar to Tramadol).Advantages: Less side effects.Used for: Indicated for controlling the pain of diabetic neuropathy.Side effects: Dependence and addiction.

References:1-The Annals of Pharmacotherapy: Overview of Oral Modified-Release Opioid Products for the Management of Chronic Pain, by: Celene M. Amabile, Bill J. Bowman.2- Bioorganic & Medicinal Chemistry: Design, synthesis, and structure–activity relationship of novel opioid κ-agonists, by: Koji Kawai et al.3- Indian J Anaesth.: Sufentanil Vs Fentanyl for Fast-Track Cardiac Anaesthesia, by: C M Deshpande et al.4- Expert Opinion on Pharmacotherapy: Mechanistic and functional differentiation of tapentadol and tramadol, by: Robert B Raffa, Helmut Buschmann.