Opioid Analgesics

HISTORY OF DEVELOPMENT

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The opium poppy was first cultivated in lower Mesopotamia in 3400 B.C.

• In 460 B.C., Hippocrates, the father of medicine stated that opium could have styptic or astringent like function in contracting the tissues and blood vessels.
• The following years saw opium cultivation waving from high to low as it demand increased in some eras whereas in some, it was considered prohibited.
• In 1827, E. Merck & Company of Darmstadt, Germany commercialises this magical substance and begins its manufacturing.
• In 1843,Dr. Alexander Wood found that injecting morphine had three times more potency and also produced instant results.
• In 1874, heroin (diacetylmorphine) was first synthesised by C.R. Wright.
• In the early 1900s, discussions and studies of heroin and morphine were rampant among scientists and doctors.
• In 1975, the endogenous opioid, encephalin, was isolated and purified by Hans Kosterlitz et al.

Ever since then, till now, opioids are a hot topic among scientists and research is constantly going on, on this drug and its derivatives.

(http://opioids.com/timeline/)

TYPES OF OPIOIDS

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Opioid is a broad term and can be classified into the following 4 types –

1. Natural
2. Semi-synthetic
3. Synthetic
4. Endogenous

1. Natural opioids, also called opiates. Natural opioids are derived naturally from the resin of opium poppy.
   
   Examples are morphine, codeine and thebaine
2. 2. Semi-synthetic opioids - They are created from natural opiates
   
   Example - diacetylmorphine (heroin), hydromorphone, benzylmorphine etc.
3. Synthetic opioids
   
   They are completely synthesised in laboratories.
   
   Examples – fentanyl. Methadone.
4. 4. Endogenous opioids
   
   They are peptides produced in the human body which mimic the functions of opioids.
   
   Examples – endorphins, enkephalins, endomorphins, dynorphins
   
   The body can also produce some more opiate derivatives like morphine, codeine, heroin etc. in very small quantities.

OPIOID RECEPTORS

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Opioids are found to bind to specific receptors found in the Central Nervous System or CNS, peripheral nervous system and in the gastro-intestinal tracts. These receptors are a group of 7TM or transmembrabe spanning GPCR or G-protein coupled receptors. These receptors mediate the functions of neurotransmitters and hormones. They have a special property of being activated both by endogenous opioid peptides and exogenous / administered opiate compounds. (Opioid receptors.,Waldhoer M, Bartlett SE, Whistler JL.

Ernest Gallo Clinic and Research Center, University of California, San Francisco, Emeryville, California 94608, USA.)

The primary receptors identified are μ or MOP, κ or KOP, δ or DOP (mu, kappa, and delta).

Of these, the μ receptor has 3 subtypes μ1, μ2 and μ3.

The other receptors that bind opioid include ε, ι, λ, and ζ (Epsilon, Iota, Lambda and Zeta) and more, making it around 17 studied opioid receptors.

Seven transmembrane structure of opioid G-protein-coupled receptor. Receptor activation by opioid receptor ligands leads to initiation of intracellular transduction pathways that include stimulation of potassium efflux, inhibition of VSCCs and inhibition of adenylyl cyclase. In this diagram the G-protein is denoted α, β, γ but the α-subunit interacts with K+/Ca2+ channel and adenylate cyclase.

(http://ceaccp.oxfordjournals.org/content/5/1/22/F1.medium.gif)

Factors Affecting Opioid Function and Opioid Receptor Activity

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How a particular opioid derivative function in the body depends on many factors, such as whether it acts as an agonist and increases the activity of the receptor; or acts as an antagonist and has either no effect on the receptor or reverses the activity of the agonist which was previously bound to the receptor and is now displaced by the antagonist.

The opioid function also depends on which receptor it binds to, its structural features and its affinity to that specific receptor.

The different receptors have different primary functions too.

• The μ receptors cause analgesic activity, respiratory depression, euphoria and addiction
• The κ receptors cause euphoria and addiction
• For instance, if morphine binds to the μ1 receptor and activates it, the supraspinal analgesics function gets triggered. If it binds to the μ2 receptor, the respiratory depression and dependence gets activated, and if it binds to the κ receptor, it activates sedation and spinal analgesia.

(http://www.news-medical.net/health/Opioid-Pharmacology.aspx)

MORPHINE

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Morphine, the active substance in opium is widely used for its analgesic properties. Its most common route of administration is intravenous and it effects are mediated by the central nervous system and not the peripheral nervous system.

(Page-23 -24, Morphine - By Gregory D. Busse, D. J. Triggle)

Morphine binds selectively to the μ receptor and further insight into the selective binding to μ1 and μ2 receptors were got by studying its effects after it is bound by naloxazone and naloxonazine.

It was found that both these substances were selective to μ1 and acted as antagonists and reversed the analgesic functions mediated by morphine, but at the same time failed to reverse the other effects of morphine such as respiratory depression and physical dependence.

(The Opiate Receptors, By Gavril W. Pasternak)

Morphine structure

Morphine has 5 rings – aromatic, cyclohexane, cyclohexene, piperidin and tetrahydrofuran. All morphine derivatives with the same basic structure will show good analgesic activity.

SUBSTITUTIONS IN THE MORPHINE RING

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The SAR or structure activity relationship of morphine has been studied by carrying out various substitutions. The largely studies substitutions include modifications in the following -

1. Aromatic ring system
2. Alicyclic ring system
3. Tertiary nitrogen
4. Ether Bridge

The key changes noted on modification of various parts of morphine occur because they affect the activity and the metabolism of morphine in vivo. The major substitutions studied are –

1. Modification of the aromatic ring system (which is essential for its activity) –

This is the phenolic hydroxyl group at position 3

Most substitutions result in a reduction of the analgesic activity that morphine has.

If C3 phenolic hydroxyl group is modified

I. 3-OH - ↓ activity

II. 3-OH → (etherification) 3-OCH3 - methyl ether → codeine - ↓ activity to 1/10th or by 90%

III. Phenolic–OH → (etherification) ethyl ether → ethyl morphine - ↓ activity to 1/10th or by 90%

IV. Phenolic–OH → (esterification) - ↑ activity

2. Modifications on alicyclic ring system

This is the alcoholic hydroxyl group at position 6

I. C-6 alpha –OH group → (methylation or esterification) →6-OCH3- hydrocodeine- ↑ analgesic activity 2 -4 times; ↑ toxicity (codeine, heroin)

II. C-8 double bond → saturation → ↑ analgesic activity (dihydromorphine, dihydrocodeine)

III. C-6 and C-14 → ethylene bridge → etorphine → ↑ 200 times of morphine

IV. 6-OH → oxidation (when 7, 8 double bond is present) → morphinone → ↓ activity (37% of morphine)

3. Modifications of Nitrogen

I. N-CH3 → replaced by N-C2H5 → ↓ activity

II. N-CH3 → replaced by hydrophobic groups like propyl, pentyl → ↑ activity

III. N-CH3 → replaced by 3-carbonyl alkyl group → naloprphine (morphine antagonist)

4. Modifications of ether bridge

I. piperidine ring → breaking→ ↓ activity

(SAR of Narcotic analgesics , NARCOTIC ANALGESIC (MORPHINE AND RELATED DRUGS) http://sar-of-drugs.wetpaint.com/page/SAR+of+Narcotic+analgesics)

MORPHINE METABOLISM AND PHARMACOKINETICS

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• The metabolism of morphine primarily occurs in the liver, and also in the brain and intestines.
• More than half of morphine (60%) is converted to morphine-3-glucuronide (M3G) by a process called glucoronidation.
• A smaller percentage (5% -10%) undergoes glucoronidation to form morphine-6-glucuronide (M6G) by the enzyme UDP-Glucuronosyltransferase-2B7 (UGT2B7).
• M6G has a stronger affinity towards the µ receptor (also called the OPRM1 receptor or the Mu Opioid Receptor 1) than morphine itself or M3G.
• Thus the ratio of M6G to morphine is a strong indicator of its potency and analgesic activity.
• M6G has an analgesic activity 2 to 4 times greater than that of morphine, while M3G is thought to have no effect. M6G is found to cross the blood brain barrier (BBB), even though it is less lipophilic than morphine.
• Hence permeability and lipophilicity are not the criteria here that justify the presence of M6G in the brain, but the function of an active transport mechanism that makes M6G cross the BBB. (Mantione KJ, Goumon Y, Esch T, Stefano GB. Morphine 6B glucuronide: fortuitous morphine metabolite or preferred peripheral regulatory opiate? Med Sci Monit. 2005;11:MS43-MS46.)
• It also shows a maximum concentration after 6 hours of IV administration. (Lotsch J, Skarke C, Darimont J, Schmidt H, Geisslinger G. The transfer half-life of morphine-6-glucuronide from plasma to effect site assessed by pupil size measurement in healthy volunteers. Anesthesiology. 2001; 95:1329-1338.)

(Role of Morphine’s Metabolites in Analgesia: Concepts and ControversiesErica Wittwer1 and Steven E. Kern, 1Department of Pharmaceutics and Pharmaceutical Chemistry, College of Pharmacy, University of Utah, Salt Lake City, UT

2Department of Anesthesiology, School of Medicine, University of Utah, Salt Lake City, UT)

ENDOGENOUS OPIOIDS

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The 4 major endogenous opioids are –

1. Endorphins
2. Enkephalins
3. Dynorphins
4. Endomorphins

Endorphins

Endorphins or the endogenous polypeptides are produced by thepituitary gland and hypothalamus, and are found in over 20 parts of the body.

The synthesis of endorphins occurs during exercise, excitement etc. The 5-endorphin has maximum affinity for the µ1 opioid receptor and lesser affinity for the µ2.

Enkephalins

Enkephalins are pentapeptides and they regulate nociception. There are 2 forms of encephalin- Met-enkephalins has Tyr-Gly-Gly-Phe-Met

Dynorphins

Dynomorphins are peptides produced in different parts of the brain. They are of 2 types – Dynomorphin A and Dynomorphin B.

They have differentfunctions based on where they are produced. Some of their roles include electrical activity patterning, oxytocin secretion inhibition, appetite control etc.

Endomorphins

They are tetrapeptides. They are 2types -Endomorphin-1 (Tyr-Pro-Trp-Phe-NH2) and Endomorphin-2 (Tyr-Pro-Phe-Phe-NH2). They have a strong affinity for the µ opioid receptor.

(Endogenous Opioids: Their Physiological Role and Receptors Anupama Koneru, Sreemantula Satyanarayana and Shaik Rizwan Department of Pharmacology, Sultan-ul-uloom College of Pharmacy, Hyderabad-034, India College of Pharmaceutical Sciences, Andhra University, Visakhapatnam-003, India)

MORPHINE ANALOGUES

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Morphine analogues are widely used because substitution of morphine’s molecular structure gives analogues of various potencies. Some of the morphine analogues are mentioned below -

1. Etorphine-

It is an oripavine derivative 1000 times as potent as morphine (http://chemistry.about.com/od/factsstructures/ig/Chemical-Structures---E/Etorphine.htm)

2. Buprenorphine

Highly potent(http://opioids.com/buprenorphine/structure.html)

3. Levorphanol

It is a type of morphinan. It lacks the E ring, 6-hydroxyl group and the 7,8 double bond(http://opioids.com/levorphanol/levorphanol.jpg)

4. Benzomorphans

They lack the C and E rings

5. Phenylpiperidines

4 phenyl piperidine Meperidine (Demerol) is a derivative of phenylpiperidine. It has one fifth or 20% the potency of morphine.(http://www.chemicalbook.com/CAS/GIF/771-99-3.gif)

Morphine antagonists

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1. Naloxone –

Strong antagonist, used to treat narcotic overdose(http://opioids.com/naloxone/naloxone.jpg)

2. Naltrexone –

Less potent antagonist, used to treat former narcotic addicts(http://opioids.com/naltrexone/naltrexone.jpg)

Chemistry of Opioid Analgesics, PHA 4220 – Neurology Pharmacotherapeutics http://www.acsmedchem.org/module/opioid.html