DEVELOPMENT OF MORPHINE AGONISTS AND

ANTAGONISTSPresented by

Tejaswi.G University College Of

TechnologyOsmania University

CONTENTS Introduction History Classification Structure of Morphine Mechanism of action Chemistry of Morphine Structure Activity Relationship Development of Morphine Analogueso Agonisto Antagonist Uses of Morphine Conclusion References

INTRODUCTION

• ANALGESIC- A drug that selectively relieves pain by acting in the CNS or on peripheral mechanism without significantly altering consciousness .

• OPIOID ANALGESICS are also known as narcotic analgesics, that act on CNS, usually used for the treatment of acute and chronic pain, for thousands of years.

• OPIUM, a dark brown resinous material from unripe seeds of Poppy.

HISTORY

• The writings of Theophrastus around 200BC describe the use of opium in medicine ; however evidence suggests that the opium is used in Sumerian cultures early as 3500BC. The initial use of opium was as a tonic, or it was smoked.

• The pharmacist Surterner first isolated an alkaloid from opium in 1803.He named it as MORPHINE, after MORPHEUS, the Greek God Of Dreams.

• Codeine, Thebaine and papavareine are other medicinally important alkaloids that were later isolated from latex of opium poppy.

• Morphine was among the first compounds to undergo structure modification.

• Ethyl morphine was introduced as a medicine in 1898.

• Diacetyl morphine(Heroin)which may be considered to be the first synthetic prodrug, was synthesized in 1874 and marketed as a non-addicting analgesic, anti-diarrheal and anti tussive agent in 1898.

 

CLASSIFICATION OF OPIOIDS

MORPHINE

• Morphine is the principal alkaloid in opium and still widely used. Therefore it is describe as prototype.Biological Source: It is obtained from

the juice or latex from the

unripe seed pods of the Papaver somniferum.

Family : Papavaraceae

Structure Of Morphine

3D Structure

2D Structure

MECHANISM OF ACTION• As morphine binds to opioid receptors,

molecular signalling activates the receptors to mediate certain actions.

• There are three important classes of opioid receptors and these are:

• μ receptor or Mu receptors - There are three subtypes of this receptor, the μ1, μ2 and μ3 receptors. Present in the brainstem and the thalamus, activation of these receptors can result in pain relief, sedation and euphoria as well as respiratory depression, constipation and physical dependence.

• κ receptor or kappa receptor - This receptor is present in the limbic system, part of the forebrain called the diencephalon, the brain stem and spinal cord. Activation of this receptor causes pain relief, sedation, loss of breath and dependence.

• δ receptor or delta - This receptor is widely distributed in the brain and also present in the spinal cord and digestive tract. Stimulation of this receptor leads to analgesic as well as antidepressant effects but may also cause respiratory depression.

Structure activity Relationship Of

Morphine

STRUCTURE

STRUCTURE

STRUCTURE

STRUCTURE

Agent class Example Action

Agonist• Morphine• fentanyl• pethidine

activation of all receptor subclasses, though, with different affinities

Antagonist naloxone devoid of activity at all receptor classes

Agonist-Antagonist

nalorphine pentazocine

agonist activity at one type and antagonist activity at another

Partial Agonist buprenorphine activity at one or more, but not all receptor types

On the basis of these receptors, drugs can be divided into four groups. a. agonists b. antagonists c. agonist-antagonists d. partial agonists

Morphine Sulfate

• Morphine sulfate is the analgesic used most often for severe,acute,and chronic pain. It is available in intramuscular,subcutaneous,oral,rectal and intrathecal dosage forms.

• 3-6 times more potent when given intramuscularly than when given orally.

• Half life -3hrs(intra muscular)

Codeine Phosphate

• It is weak µ agonist, methyl ether of morphine.

• Activity:20% that of Morphine• Half Life: 3.5hrs• Treats: moderate pain, cough, diarrhoea.• Trade name:PANADOL

Hydromorphone Hydrochloride

• Activity: potent µ agonist,(8 times greater than morphine)

• Half life : 2.5hrs(Parenteral)• 4hrs(oral)• Trade Name: Dilaudid

Oxymorphone Hydrochloride

Activity: potent µ agonist,(10 times greater than morphine)

• Half life:3-4hrs• Treats: moderate to severe pain• Because of its 14-hydroxy group, has low

antitussive activity.• Trade Name: Numorphan

Oxycodone Hydrochloride

• Activity: it is about equipotent with morphine

• Half life: 4hrs• Treats: Moderate to severe pain• Trade Name: Oxycontin,Percodan

Meperidine Hydrochloride

• Activity:It is µ agonist having 1/10th of potency of Morphine

• Half life:3-4hrs• Treats:extensively used in Obstrics,when

given I.V respiratory depression of newborn child is minimised.

• Trade name:Demerol

Fentanyl Citrate

• Activity:it is µ agonist and 80times greater potency than morphine

• Treats:Fentanyl patch is used for chronic pain.Used in combination with Nitrous oxide for balanced anaesthesia.

• Trade Name:DUROGESIC

Buprenorphine Hydrochloride

• Activity:20-50 times more potent than morphine,partial agonist at µ,k receptors, receptors but antagonises at ð receptors.

• Treats: treatment of those addicted to opioids, such as heroin  and oxycodon, but it may also be used to treat pain.

• Trade Name:Suboxone

Pentazocine

• Activity:It is Weak antagonist (1/30th potency of naloxone),at receptors and agonist at k receptors.

• Treats: used to relieve moderate to severe pain. It may also be used before surgery or with a general anesthetic.

• Trade Name:Talwin

Naloxone

• Activity: it is a pure opioid antagonist.• Treats:It is drug of choice for treating

Opioid respiratory and CVS depression• Trade name:Narcan

Nalbuphine Hydrochloride

• Activity: It is an antagonist at receptors and an agonist at k receptors.

• Treats: Morphine Poisoning, severe to moderate pain.

• Trade name: Nubain

Before Addiction After Addiction

CONCLUSION Finally we conclude that Morphine structure has

phenanthrene nucleus. Removal of 3-OH group reduces analgesic

activity. Acetylation of 3-OH and 6-OH group produces

very potent lipophilic compound. 6-OH and 7,8 double bond is not required for the

analgesic activity,elimination enhances the activity.

N-Methyl group substitution with larger alkyl groups reduces the activity.Substitution with larger araalkyl group increases the activity.

N-Methyl group replacement with alkyl,methyl cyclopropyl group - antagonist activity.

REFERENCES

• An Introduction to Medicinal Chemistry –• Graham L. Patrick, 4th Edition.• Organic Chemistry Natural Products – O.PAgarwal, Volume – 1.• /www.drugbank.ca/ • https://en.wikipedia.org/wiki/Morphine