Morphine: Structure, Synthesis, and Mechanism of Action

Dilbir Sekhon

Organic Chemistry 12B

April 28, 2006

http://dilbir2006.tripod.com/

Abstract

Morphine, the principal active agent in opium, is a powerful opioid analgesic drug. Like other opiates, morphine acts directly on the central nervous system (CNS) to relieve pain, and at synapses of the arcuate nucleus, in particular. Side effects include impairment of mental performance, euphoria, drowsiness, lethargy, and blurred vision. It also decreases hunger, inhibits the cough reflex, and produces constipation. Morphine is usually highly addictive when compared to other substances, and tolerance and physical and psychological dependence develop quickly. Patients on morphine often report insomnia and nightmares. The word derives from Morpheus, the god of dreams in Greek mythology.

Outline

I.  History

II.   Biological and Biochemical effects

III.  Addiction

IV.  Physical and Chemical Properties of Morphine

V.   Synthesis of Morphine: Cuprate Conjugate Addition

VI. Synthesis of Morphine: Eschenmoser-Claisen Rearrangement

VII. Mechanism of Action for Morphine

VIII. Methods of Use

IX.   Legality

X.    Conclusion

History    Morphine has been used in the form of opium for centuries.  It is

unknown exactly who, when, or where opium was first used or discovered, but the date can be narrowed to around 4000 BC.  It was used to relieve anxiety and pain.  It was also used to induce sleep and give a feeling of well being and peace.  The first recorded use of opium for medical purposes was in 200 BC.

    In the 16th century, a Swiss physician name Paracelcus experimented with the medical value of opium.  He decided that its medical value was of such magnitude, that he called it Laudanum.  Laudanum comes from the Latin word "laudare".  Laudare means "to praise".  He did not know of its addictive properties.

    1803 can be seen as the true "birth date" or discovery date of Morphine.  In 1803, Serturner, a German pharmacist, identified and isolated the main ingredient of opium, Morphine.  He called this alkaloid "Morphia" after Morpheus, the Greek God of Dreams.  The name "Morphine" is now used instead of Morphia because of the standard that all alkaloids end in "-ine".

Biological/Biochemical EffectsLow Doses (single doses of 5 - 10 mg administered by S.C or IM injection in non-tolerant users)

CNS, behavioral, subjective :suppression the sensation of and emotional response to pain; euphoria; drowsiness, lethargy, relaxation; difficulty in concentrating; decreased physical activity in some users and increased physical activity in others; mild anxiety or fear; pupillary constriction, blurred vision, impaired night vision, suppression of cough reflex.

Respiratory: slightly reduced respiratory rate.

Gastrointestinal:nausea and vomiting; constipation; loss of appetite; decreased gastric motility.

Other:slight drop in body temperature; sweating; reduced libido; prickly or tingling sensation on the skin (particularly after intravenous injection).

Duration: 4 - 5 hours

Dependency Potential: high, continued use results in both psychological and physical dependency

Addiction

Morphine is highly addictive. Tolerance (the need for higher and higher doses to maintain the same effect) and physical and psychological dependence develop quickly. Withdrawal from morphine causes nausea, tearing, yawning, chills, and sweating lasting up to three days. Morphine crosses the placental barrier, and babies born to morphine-using mothers go through withdrawal.

Physical and Chemical Properties of Morphine Morphine is an opioid receptor

agonist – its main effect is binding to and activating the µ-opioid receptors in the central nervous system. Activation of these receptors is associated with analgesia, sedation, euphoria, physical dependence and respiratory depression. Morphine is also a κ-opioid receptor agonist, with this action associated with spinal analgesia and miosis.

Morphine is legally available only in the form of its water-soluble salts. Most common are morphine sulfate and morphine hydrochloride. Both are fine white crystalline powders, bitter to the taste. Both are soluble in water

and slightly soluble in alcohol. Morphine

Synthesis of (-)-Morphine by Cuprate Conjugate Addition

Will Draw in these pictures

Synthesis via Eschenmoser-Claisen Rearrangement Will draw in these pictures

Mechanism of Action: Morphine Opiates elicit their powerful

effects by activating opiate receptors that are widely distributed throughout the brain and body. Once an opiate reaches the brain, it quickly activates the opiate receptors that are found in many brain regions and produces an effect that correlates with the area of the brain involved. Two important effects produced by opiates, such as morphine, are pleasure (or reward) and pain relief. The brain itself also produces substances known as endorphins that activate the opiate receptors.

Morphine mimics endogenous neurotransmitters (endorphins). Morphine binds to specific morphine-like (endorphin) receptors (EndR).

Methods of Use

Morphine may be given parenterally as subcutaneous, intravenous, or epidural injections. The military sometimes issues morphine loaded in an autoinjector.

Orally, it comes as an elixir, concentrated solution, powder (for compounding) or in tablet form. Morphine is rarely supplied in suppository form. Due to its poor oral bioavailability, oral morphine is only one-sixth to one-third of the potency of parenteral morphine. Morphine is available in extended-release capsules for chronic administration, as well as immediate-release formulations.

Legality

In the United Kingdom, morphine is listed as a Class A drug under the Misuse of Drugs Act 1971.

In the United States, morphine is classified as a Schedule II drug under the Controlled Substances Act.

Internationally, morphine is a Schedule I drug under the Single Convention on Narcotic

Conclusion

In ancient medicine, some plant derivatives

were used to alleviate pain including: alcohol, cannabis, mandrake, and opium. Over the past two centuries, opium and its derivatives

have become the most widely used analgesics for severe pain. Since its isolation from opium almost 200 yr ago, morphine remains the most widely used analgesic and the standard against which all new opioids for postoperative pain relief are compared.

Bibliography

Morphine Apparently in Your Head- Wired Magazine article about endogenous production of morphine

The Influence of Morphine and GR89696 on NMDA receptor Phosphorylation, Journal of Undergraduate Research.Volume 5, Issue 5 - February 2004

http://en.wikipedia.org/wiki/Morphine#Pharmacology http://www.bartleby.com/65/mo/morphine.html http://www.chamisamesa.net/morphine.html