1. Opioids Opium poppy cultivation
Opium poppy capsule (Papaver somniferum), the source of both opium and the poppy seeds you find on bread
Namut Ali inhales heroin in a cemetery near Quetta. Heroin coming across the Afghan border to Pakistan costs only about $1 a gram. (By Adrees Latif, Reuters)

2. History Papaver somniferum
The term opium is from the Greek opion, meaning, poppy juice, Papaver is from the Latin name for the poppy, and somniferum is Latin, meaning, to produce sleep
Morphine was first isolated in 1803 from juicy exhudates of poppy by Friedrich Serturner, a pharmacist, and named after Morpheus, the Greek god of dreams
Characterized in 1925
Codeine was isolated in 1832 and papaverine in 1848
Two major types of alkaloids: phenanthrenes (1), e.g., epoxymorphinans or morphine), and the benzylisoquinolines (2)

3. Genesis of new narcotic agonists and antagonists through molecular modification

4. Opiate/Opioid
“Opiate” (used until 1980s) means drugs derived from opium – morphine, codeine, and their semi synthetic analogs
“Opioid” was coined after discovery, in the mid-1970s, of peptides in brain that had morphine–like pharmacologic activity that include natural and synthetic compounds and peptides
Opioid receptors - that bind these opioids to elicit morphine-like agonistic or antagonistic activities
“Narcotic” derived from the Greek word, narkōtikos, meaning to be numb, and was originally applied to any drug which induced sleep
Thus morphine–like analgesics (opioids) are called narcotic analgesics
narcotic was also defined legally (Harrison Narcotics Act, 1914) and it was used to refer to drugs, such as opioids, cocaine and marijuana, that were controlled in a more stringent manner than other drugs
Now they are classified by DEA as Schedule I drugs

5. Opioid Peptides
Greek, kephalē, which means “head” gives the name enkephalins. 2 enkephalins differ in the fifth amino acid one has a Methionine and the other a Leucine residue: Met–enkephalin and Leu–enkephalin
pro–enkephalin and few more endogenous peptides with opioid activity have been found, the endorphins and the dynorphins,
The opioid receptor has been subtyped into three distinct types based on these three types of endogenous peptides: (Endorphins –Mu, dynorphins – kappa, enkephalins – delta)
In all three types of peptides the amino terminus is always the same four amino acids (H2N–Tyr–Gly–Gly–Phe–)

6. Opioid Receptors Three major subtypes of opiate receptor
μ (Mu, OP3): the most important receptor, Encoded by the MOR-1 gene, subtyped into μ1 and μ2. Agonists cause Supra–spinal & spinal analgesia, respiratory depression, euphoria, emetic effects, physical dependence, and constipation. Morphine and endorphines are selective agonist and naloxone is selective antagonist
δ (Delta, OP1): Encoded by the DOR-1 gene. Subtyped into δ1 and δ2. Spinal analgesia, GI motility, motor integration, cognitive functions, mood driven behavior are the agonist properties. D-Ala-D-Leu-enkephalin is a selective agonists while naltrindole is a selective antagonist
κ (Kappa, OP2): Learning & memory, spinal analgesia, sedation, neuroendocrine secretions. N/OFQ or ORL-1 receptor. Dynorphins are selective agonists. .

7. Schematic Representation of an Opioid Receptor
Site “A” is an additional lipophilic site that binds with the phenyl ring on phenylalanine of the endogenous opioid peptides. This explains receptor interaction of some of the opioid drugs
Site” D” binds the tyrosine residue of the endogenous opioid peptides: Flat, hydrophobic with an adjacent hydrogen bonding site for hydroxyl on phenyl ring that binds ring “A” of morphine
Site “B” is an anionic site that binds the protonated nitrogen of the pyridine ring (ring “D”) found in morphine
Site “C” is a cavity that accomodates C15 of morphine

8. Ring Nomenclature and Numbering
Removal of ring C
Removal of ring E
Removal of ring B
Adding a ring F
Removal of ring D

9. Epoxymorphinans Ring numbering and nomenclature:
General structure
Morphine
Ring numbering and nomenclature:
Based on phenanthrene thus these three rings are labeled A, B and C, other two are labeled D and E
Morphinan (1946) refers to rings A, B, C and D of morphine, hence, epoxymorphinans (more specifically the 4,5–α–epoxymorphinans)
Rings B and D of morphine is termed Morphan, Ring A is aromatic and, thus, flat, Ring C is in the boat confirmation due to the double bond, Ring D is the nitrogen-containing piperidine ring, Ring E is the ether or epoxide
5 chiral centers (5, 6, 9, 13, 14), hence, 25, or 32 stereoisomers (16 are possible due to steric hindrance).
(–) Morphine is naturally produced, the absolute configuration was established in 1955 as 5R, 6S, 9R, 13S, 14R
The configuration at C9 is the most important, which determines the orientation and distance between the protonated nitrogen and the phenyl ring. In most cases the more active isomer is levorotatory. Usually the isomers with an S configuration are dextrorotatory

10. SARs of Epoxymorphinans
Modifications of this class involve C3, C6, C7, C8, C14, and the piperidine Nitrogen
The earliest molecular modifications were simple, such as esterification, etherification, and increasing the length of the N–substituent
The net results were compounds with greater potency but also greater toxicities and additional liabilities and side effects
Molecular modifications may be divided into three groups:
Ring “A”,
Ring “C”
Ring “D”

11. 1. Ring “A” Modifications
A free phenolic OH is optimal for μ receptor (analgesia) affinity, but will decrease LWPC and also leads to first pass glucuronidation leading to poorer oral bioavailablity. Example: morphine
Conversion of the OH to ether causes decease in μ receptor affinity. Thus codeine is a prodrug for its analgesic effect. The larger the group the slower this proceeds and therefore, the larger the group the less μ receptor affinity
However, etherification increases antitussive effectiveness and do not need to remove the alkyl group. This is probably through a different receptor
Etherification also increases LWPC. The larger the lipophilic substituent the higher the LWPC and thus increased bioavailability and cannot glucuronidate. Example: codeine

12. Conversion to an ester creates a prodrug which must be hydrolyzed at C3 to interact with the receptor. For diacetyl morphine (heroin) the ester at C6 does not have to be removed for the receptor interaction. The C3 is more susceptible to hydrolysis as phenyl is an electron withdrawer
Such diacetyl derivative has increases LWPC and thus enhanced penetration through the BBB and thus euphoric rush which makes the compound more popular for abuse. Example: heroin
Removal of ring E increases LWPC. So, in general, all else being equal, a morphinan is overall more potent than the corresponding epoxymorphinan. The ether bridge does not interact with the receptor so does not affect μ receptor affinity. Example: morphinans

13. 2. Ring C Modifications
Natural conformation of C6 Hydroxyl is α. In this conformation it interacts, poorly, with a hydrophobic region of the receptor. The interaction is not favorable since the hydroxyl is not lipophilic. Addition of methyl group increases LWPC and μ receptor affinity. Example: heterocodeine, a structural isomer of codeine, which is more potent than even morphine
Inversion to the β conformation increases μ receptor affinity as points away from the lipophilic region so does not interact unfavorably
Removal of this OH increases μ receptor affinity it also removes unfavorable interaction with the hydrophobic site

14. Oxidation decreases analgesic potency, which still possesses a polar oxygen, and apparently interacts more unfavorably with the hydrophobic region on the receptor
Replacing hydroxyl with methyl or methylene increases μ receptor affinity, again, due to better hydrophobic interaction. Example: nalmefen. Introduction of additional OH at C14 increases μ receptor affinity due to an increased hydrogen bonding to an allosteric site
The C7, C8 (Δ7) olefinic bond saturation changes LWPC and μ receptor affinity. Saturation gives a slight increase in LWPC and also ring “C” goes from boat to chair conformation that changes the 3D position of C6 hydroxyl. This gets rid of the unfavorable hydrophilic–hydrophobic interaction. Thus, this also increases μ receptor affinity
Saturation plus oxidation of C6 oxygen produces an increase in μ receptor affinity. The ketone is more rigid and held away from the hydrophobic region. May even interact with an adjacent hydrophilic region

15. Removal of ring C increases LWPC
Removal of ring C increases LWPC. Removed C6 hydroxyl does not interact with the hydrophobic site on the receptor unfavorably so it increases μ receptor affinity. So, in general, all else being equal, benzmorphans are more potent than morphinans.
Introduction of ring F increases LWPC. All else being equal, the oripavines are more potent than the epoxymorphinans. Example: etorphine

16. 3. Ring D Modifications
“R” configuration α to the N (C9) is optimal for μ receptor affinity
Removal of N-methyl decreases LWPC, Quaternization decreases LWPC tremendously, N-oxide decreases LWPC which is more polar through resonance where there is an N+ and O– form. What is the effect?
Increasing size of N-alkyl decreases μ receptor affinity through steric hindrance but increases LWPC. As length of N-alkyl increases, μ receptor affinity decreases. Until the chain is about 5 carbons (better if aralkyl) then μ receptor affinity starts to increase slightly due to induced-dipole, induced-dipole interaction with allosteric “A” site, which is a phenyl ring.

17. Branching, unsaturation or strained ring structures in the N-alkyl substituent leads to antagonism or, at the very least, partial agonism, for at least one of the opioid receptors. (Nalorphine, Naltrexone)
Methylnaltrexone (relistor, approved in Apr 2008) is a quaternized compound which act peripherally as µ-opioid antagonist. Thus It has been approved for treating (SC and oral) opioid drug induced constipation without affecting analgesia or precipitating the withdrawal syndromes of opioids.
Substituents that are 3 carbons in length have higher μ receptor affinity as an antagonist than those with 4 carbons. Optimal antagonistic potency is obtained when the N–substituent chain is 3 carbons in length. Includes allyl and methyl isopropyl groups. Example: nalorphine
At 5 carbons antagonism is lost and agonism returns due to interaction with site “A”
Removal of C15 (breaking ring D) decreases μ receptor affinity

18. Summarizing the Effects of altering chain length on N of morphine structure

19. Morphinans
The morphinans were introduced in They are morphine without the ether link but are produced synthetically. Numbering system is the same as with morphine. Since these compounds are synthetic they are obtained as racemates. The more potent isomer has an R configuration α to the nitrogen (C9 is R)
Numbering system is similar to epoxymorphinans

20. SAR of Morphinans
Epoxymorphinans and morphinans interact with the receptor in a similar fashion and thus exhibit similar pharmacological profiles and SARs especially in the C3 hydroxy, C14 hydroxy, and the N–substituent. (–)–N–Methylmorphinan possess high degree of analgesic activity, i.e., the ether bridge is not necessary for activity, introduction of a phenolic OH increases potency
The racemic mixture is known as racemorphan and was marketed as Dromoran™.
The levorotatory isomer with R configuration alpha to the nitrogen is known as levorphanol. It is 6 to 8 times as potent an analgesic as Morphine. It is also a potent antitussive. This high potency is due to (a) a higher LWPC (1300 vs 8) (b) loss of the ether oxygen and the C6 hydroxyl (c) It also has higher receptor affinity. Advantages over Morphine include better oral bioavailability and a longer duration of action, but it has higher toxicities
The dextro isomer, dextrorphan is devoid of analgesic activity and associated liabilities but remains a potent antitussive. It is further substantiating the belief that analgesia and antitussive effect are mediated through different receptors. The dextro isomer was O–methylated to increase its antitussive potency which is marketed as dextromethorphan. Dextromethorphan is said to be as potent as Codeine as an antitussive without respiratory depression and associated side effects

21. >>
The N–allyl derivative, levallorphan is a potent antagonist at μ receptors, five times as potent as nalorphine
Hanche
Butorphanol has higher μ receptor affinity compared to morphine due to the C14 hydroxyl but with little dependence liabilities and limited respiratory depression. This drug is a mixed agonist/antagonist - κ agonist, μ antagonist. Susceptible to significant first pass metabolism and administered parenterally or intranasally. κ Agonists have lower ceiling analgesia effects and are not as effective as μ agonist in severe pain.

22. Benzomorphans
Introduced in the 1960s and are purely synthetic. Numbering system changed
In this series, the effects on the 2’ position and N–substituent are the same as Morphine i.e., similar binding with receptor
Unlike previous classes the (+)–isomer retains significant analgesic potency, but the (–)–isomers are still more potent which have the “R” configuration at C1 (C α to N like Morphine)
R2 and R3, are essential for μ receptor affinity. R3 is down because the piperidine ring is up but R2 may be up or down. The cis (R2 & R3) isomers are called α and the trans isomers are called β. The α isomers are superimposable on morphine, however, the β isomers have higher μ receptor affinity than the α isomers. Still, α isomers have higher μ receptor affinity compared to morphine (b > a > morphine)
Both α and β benzomorphans also have a higher LWPC than morphine further adding to their overall potency. The β isomers have higher dependence liabilities than α isomers. Therefore, clinically the weaker α isomers are used.

23. Pentazocine, marketed in the US m anta, k ago
Metazocine is the prototype. The LWPC is higher than morphine
Cyclazocine (methylcyclopropyl) is a potent mixed agonist/antagonist. High LWPC and high incidence of hallucinations.
Phenazocine (a μ agonist marketed in Europe) is 14X more potent than morphine due to phenethyl group interaction with “A” site and due also to its increased lipophilicity
Ketazocine, not marketed in the US, has high affinity for the κ receptor and gives the receptor its name
Pentazocine, marketed in the US m anta, k ago

24. Phenylpiperidines
Meperidine is the prototype; potency about 20% of morphine and higher LWPC. Short duration of action due to metabolism of its ester and % bioavailable. About 1/3 as potent orally as compared to parenteral
due to free rotation around the σ bond molecule is extremely flexible. Unlike all previous rigid series (phenyl ring was axial to the piperidine) the phenyl in this class moves to the less energetic equatorial position (<0.1% of the molecules would have a phenyl–axial conformation at any time, not enough to account for its potency). This implies that it may bind to the receptors in a different way than the rigid opioids, with different SAR patterns. This also accounts for the low receptor affinity and the lack of antitussive effect.
Meperidine is believed to bind with site “A” and the anionic site “B”. Binding with site “A” is not as effective as binding to site “D”

25. SAR of Phenylpiperidines
Removal or replacement of the phenyl with alkyl, aryl, or aralkyl groups always decrease affinity for site “A”.
Separation of the phenyl and the ester groups decrease potency. This modifications result in a change in the distance between the nitrogen and the phenyl ring, a critical feature. This decreases the ability to bind site “A” and “B” simultaneously.
Insertion of a meta hydroxyl does increase potency by 50%. Thus Bemidone has higher affinity for the “A” site than meperidine possibly due to hydrogen bonding to an adjacent site
Conversion of the ester to a ketone increases potency and duration of action by increasing metabolic stability, esters can be hydrolyzed but ketones cannot. Example: ketobemidone

26. Another molecular modification that stabilizes the molecule is reversal of the ester. The Meperidine reverse ester (MPPP, N–methyl phenyl–4–propionoxy piperidine) has a longer duration of action due to increased resistance to ester hydrolysis. However, reversal of the ester group converts a stable group into a leaving group in vitro that produce MPTP upon decomposition, which is converted to MPP+ by MAO–B
Introduction of a methyl to MPPP at position 3 results in stereoisomers having different potencies. The trans methyl is called Alphaprodine and the cis isomer is Betaprodin. Their respective potencies are 5 and 14 times Meperidine
In Alphaprodine the phenyl is axial while it is equatorial in Betaprodine. This may account for the difference in potency. The 3–methyl affects the conformation of the phenyl ring with respect to the nitrogen decreasing μ receptor affinity

27. SARs for the N–substituent
The SARs for the N–substituent are similar to epoxymorphinans. Introduction of aralkyl substituents markedly increase potency
Expansion or contraction of the ring to seven or five members gives compounds with analgesic activity but less μ receptor affinity due to a change in relationship between the nitrogen and the phenyl ring
Diphenoxylate is highly lipophilic. However, in regular doses has no CNS activity due to (a) highly protein bound and sequester in the lipid bilayer, (b) rapidly hydrolyzed to the carboxylic acid Diphenoxin which can not penetrate the blood brain barrier
Loperamide has high LWPC and also free of all CNS effects due to high protein binding and twice as potent as Diphenoxylate. Further, the high lipophilicity result in slow dissolution resulting in slow absorption and 40% bioavailability. The lack of water solubility prevents drug abuse because it can not be injected

28. Phenylpiperidine Type Antagonist
Alvimophan (Entereg) is the first phenyl piperidine type µ-antagonist with limited CNS effect and thus lower opioid drug induced side effects especially constipation. It does not affect the analgesia precipitate withdrawing syndrome. It got FDA approval in May It binds the GI µ-receptor strongly but dissociates slowly thus exhibiting selective peripheral activity. Thus unlike methylnaltrexone, which can not deliver into brain due to positive charge, its selectivity is kinetically controlled.

29. Anilidopiperidines
Moving the phenyl ring from direct attachment to the piperidine ring by one atom to nitrogen on the side chain allows for the phenyl ring to assume the more favorable axial conformation. Thus, the phenyl ring of the anilidopiperidines binds the “D” site similar to the morphine “A” ring. 3-OH is not essential for binding to this site. This class includes some of the most potent synthetic analgesics
Fentanyl: 50 to 100 times more potent than morphine. It has high μ receptor affinity due to binding at “A”, “B” “C” and “D” sites. High LWPC and thus can be absorbed through skin or oral mucosa. N at C4 and the alkyl through NCO bond increases μ receptor affinity by correctly orienting the phenyl ring
Remifentanyl: Esters on N and at C4 lead to rapid inactivation by plasma esterases in consistent with the soft drug / antedrug concept

30. Phenylpropylamines
The prototype is Methadone, can be viewed as a ring “D” opened phenylpiperidines. When ring D of Morphine was opened there is a total loss of activity but racemic Methadone is equal to Morphine in analgesic potency. Both phenyl rings required for potency. Removal of one sharply reduces potency, may help correct positioning of one phenyl with correct spacing to the protonated amine for the anionic site
The phenyl ring of the phenylpropylamines binds the “D” site analogous to the “A” ring of morphine rather than the “A” site as we saw with the phenylpiperidines. They have high LWPC, low first pass due to metabolically stable; it is not an ester but a ketone. Also has a long half-life

31. SAR of Phenylpropylamines
N-substitution:
Generally the dimethylamino gives optimal potency. The diethylamino derivative is less potent but 5 and 6 membered alicyclic basic units have comparable activity to the dimethylamino group
The two carbon chain between the basic nitrogen and the quaternary carbon is the optimal length
Removal of the 6–α–methyl (normethadone) decreases potency
Moving the 6 (a)-methyl to position 5 (β) gives Isomethadone which has 65% of the potency
Ketone side chain is important for activity, removal or altering its length abolishes or significantly decrease potency
Reduction of the ketone produces Methadol with decreased potency
All the above modifications result in changing the distance and orientation of the basic amine and the phenyl group

32. Potency decrease dramatically
Acetylating the alcohol produce a more potent analgesic
The levorotatory isomer is marketed as Levomethadyl acetate. A single dose can suppress withdrawal for 3 days and is used in rehabilitation programs. The levo isomer is 5 times more potent than the dextro isomer
Methyl has been moved to the β position
Phenyl replaced by a benzyl
Ketone is replaced by an ester
Propoxyphene
Potency decrease dramatically
The introduction of a benzyl creates a second chiral center with four possible isomers
The analgesic activity resides primarily in the (+) isomer with 2S,3R configuration. It is marketed as Darvon™. It has 1/8 the potency of Methadone and 2/3 of Codeine. Has lower addiction liabilities and toxicities
The (–) isomer with 2R,3S configuration was used as an antitussive called Novrad™ which lacks the classical opioid characteristics and a pure antitussive
The napsylate salt is used because it is water insoluble and is less likely to be abused by injection

33. Tapentadol (Nucynta) is a simplified structure approved in November 2008 as narcotic analgesic. It has a dual mechanism of action as a µ-opioid agonist as well as a NE reuptake inhibitor with analgesic potency comparable to that of morphine with a more tolerable side effect profiles.

34. Oripavines
SAR is same as epoxymorphinans. Ring F introduces additional lipophilicity. C7 attachments can increase LWPC. If they are large enough they may begin to bind to site “A” and increase μ receptor affinity. This is especially true if an aromatic ring such as a phenyl is attached
Buprenorphine, containing a large alkyl moiety, is times more potent than morphine, has a longer duration of action, does not produce severe respiratory depression, and has low abuse potential
Etorphine is about 6000 times more potent than morphine, because it is 300 times more soluble in lipids and its affinity for opioid receptor is 20 times stronger and its use is restricted to the capture of large animals

35. Case stories
Case 1. Late on Sunday afternoon, BC, a 26-year-old man, was playing softball with is church team. While running to second base, BC was hit on the right side of the face with a thrown ball, which resulted in a broken jaw in three places. He was taken to the emergency room of a local hospital in considerable pain. An oral surgeon was finally located at a party and asked to come to assess and repair the damage. BC was administered an analgesic by injection while for the oral surgeon. The oral surgeon wired BC’s jaw together, with restriction to a liquid diet for 6 weeks; BC was then sent home.
1. Explain the four drugs shown (1-4) with regard to their suitability for analgesia in this case. Rationalize your best choice and discuss why the others were excluded.

36. Case 2. As a pharmacist specializing in home-health care, you are working with a 25-year-old terminal cancer patient, CB, who has recently moved to your city. For pain management, she had previously been stabilized on structure 1 (4 mg q 4-6 h), but her new physician has written for another agent, 2.
1. What is the opioid receptor activity profile of each analgetic drawn?
2. What therapeutic advantages and disadvantages would be realized with a switch to agent 2.
3. Would you fill this new prescription? Why, or why not?
4. Should you be worried about the possibility of opioid addiction in CB?

37. Study Guide Structures and function of pro- and met-enkephalins
Different types of opioid receptors, their functions and agonists/antagonists.
Drug-opioid receptor interactions
Different types of opioid analgesics with structures
SAR of epoxymorphinan. What happens if you etherify or esterify the phenolic –OH and/or aliphatic –OH?
Know all about methylnaltrixone
Effect of altering chain length on N of morphine and related drugs.
Why morphinans are more potent than epoxymorphinans? (SAR)
How do you differentiate between oipiod agonist and antagonist from the given structure?
Whicg phenylpiperidin derivatives are neurotoxic and which ones are not? Why?
Why loparamide and diphenoxylate are not centrally active? What are they used for?

38. Study Guide Cont. Know all about Alvimophan (Entereg).
Different types of opioid receptors, their functions and agonists/antagonists.
What are anilidopiperidine analgesics? Are they more or less potent than morphine?
Structures and SAR of phenylpropylamine derivatives as narcotic analgesics.
Which isomer of propoxyphen is analgesic and which one is antitussive?
Know all about dual acting Tapentadol (Nucynta)
Why oripavines are highly potent narcotic analgesics? What are they mainly used for?