This document summarizes the structure-activity relationships of various opioid receptor agonists and antagonists. It describes the key structural features of morphine that contribute to its opioid activity. It then discusses various analogues and derivatives of morphine, including codeine, heroin, oxycodone, levorphanol, fentanyl, methadone, loperamide, naltrexone, naloxone, buprenorphine, and others. It also briefly mentions the proposed Beckett-Casy model of the opioid receptor and how morphine may interact with it.

1. compiled by
Prof. Jayshree Patil
Dept. of P’ceutical Chemistry
AIKTC, School of Pharmacy, New Panvel
Opioids

2. CONTENTS
3.1 Opioid peptides (Self study) Different types of opioid receptors, Potuguese
and Becket Casy model
Agonists, partial agonists and antagonists of these receptors
Morphine, codeine, levorphanol, buprenorphine, phenazocine, pentazocine,
meperidine*, alpha and beta prodine, pheniridine, anileridine, fentanyl,
methadone, dextropropoxyphene*, tramadol, nalorphine, naloxone, naltrexone,
flupirtine
Antidiarrhoeals (Self study) : loperamide, diphenoxylate

3. https://www.bjanaesthesia.org/article/S0007-0912(17)33146-X/fulltext
https://www.researchgate.net/figure/Opioid-receptors-and-their-functions_tbl1_262342697

4. Structure–Activity Relationships
of µ Receptor Agonists
(Morphine)

5. Morphine is the prototype opioid.
It is selective for µ opioid receptors.
The structure of morphine is composed of five fused rings, and the molecule has five chiral
centers with absolute stereochemistry 5(R), 6(S), 9(R), 13(S) and 14(R).
The naturally occurring isomer of morphine is levo-[(–)] rotatory. (+)-Morphine has been
synthesized, and it is devoid of analgesic and other opioid activities.

6. The A ring and the basic nitrogen, which exists predominantly in the protonated (ionized)
form at physiological pH, are the two most common structural features found in compounds
displaying opioid analgesic activity.
The aromatic A ring and the cationic nitrogen may be connected either by an ethyl linkage
(9,10-positions of the B ring) or a propyl linkage (either edge of the piperidine ring that forms
the D ring).
The A ring and the basic nitrogen are necessary components in every potent µ agonist known.
These two structural features alone are not sufficient for µ opioid
activity, however, and additional pharmacophoric groups are
required.
In compounds having rigid structures (i.e., fused A, B, and D
rings), the 3-hydroxy group and a tertiary nitrogen either greatly
enhance or are essential for activity

7. Nitrogen Atom
The substituent on the nitrogen of morphine and morphine-like structures is
critical to the degree and type of activity displayed by an agent.
A tertiary amine usually is necessary for good opioid activity.
The size of the N-substituent can dictate the compound's potency and its agonist versus antagonist
properties.
Generally, N-methyl substitution results in a compound with good agonist properties.
Increasing the size of the N-substituent to three to five carbons (especially where unsaturation or small
carbocyclic rings are included) results in compounds that are antagonists at some or all opioid receptor
types.
Larger substituents on nitrogen return agonist properties to the opioid. An N-phenylethyl–
substituted opioid usually is on the order of 10-fold more potent as a µ agonist than the corresponding N-
methyl analogue.

8. 3-Phenolic Hydroxy Group
A number of the structural variations on morphine have yielded
compounds that are available as drugs in the United States. The most
important of these agents, in terms of prescription volume, is the alkaloid
codeine.
Codeine, the 3-methoxy derivative of morphine, is a relatively weak µ
agonist, but it undergoes slow metabolic O-demethylation to morphine,
which accounts for much of its action.
Codeine also is a potent antitussive agent and is used extensively for this
purpose.

10. 3,6-diacetyl derivative of morphine (heroin)
At the time of its introduction, heroin was described as
“preferable to morphine because it does not disturb digestion or
produce habit readily.” Heroin itself has relatively low affinity for
µ opioid receptors; however, its high lipophilicity compared to
morphine results in enhanced penetration of the blood-brain
barrier.
Once in the body (including the brain), serum and tissue esterases
hydrolyze the 3-acetyl group to produce 6-acetylmorphine.
Repeated use of heroin results in the development of tolerance, physical dependence, and acquisition of a
drug habit that often is destructive to the user and society.
In addition, the use of unclean or shared hypodermic needles for self-administering heroin often results in
the transmission of the HIV, hepatitis, and other infectious diseases.

11. C Ring
Changes in the C-ring chemistry of morphine or codeine can lead to compounds with
increased activity.
Hydromorphone is the 7,8-dihydro-6-keto derivative of morphine, and it is 8 to 10 times
more potent than morphine on a weight basis. Hydrocodone, the 3-methoxy derivative of
hydromorphone, is considerably more active than codeine.
14α-Hydroxy-6-Keto Derivatives
The opium alkaloid thebaine can be synthetically converted to 14α-hydroxy-6-keto
derivatives of morphine. The 14α-hydroxy group generally enhances µ agonist properties
and decreases antitussive activity, but activity varies with the overall substitution on the
structure.
Oxycodone, the 3-methoxy-N-
methyl derivative, is about as potent
as morphine when given parenterally Oxymorphone is the 3-hydroxy-N-methyl derivative,
and it is 10 times as potent as morphine
Substitution of an N-cyclobutylmethyl for N-methyl and reduction of the 6-keto group to 6α-OH of
oxymorphone gives nalbuphine, which acts through κ receptors and has approximately half the analgesic
potency of morphine. Nalbuphine is an antagonist at µ receptors. Interestingly, N-allyl- (naloxone) and N-
cyclopropylmethyl- (naltrexone) noroxymorphone are “ pure” opioid antagonists. Naloxone and naltrexone
are slightly µ receptor selective and are antagonists at all opioid receptor types.

12. 3,4-Epoxide Bridge and the Morphinans
Removal of 3,4-epoxide bridge in the morphine structure results in
compounds that are referred to as morphinans.
The synthetic procedure yields compounds as racemic mixtures and only the
levo-(–)-isomers possess opioid activity.
The dextro isomers have useful antitussive activity.
The two morphinan derivatives that are marketed in the United States are
levorphanol and butorphanol.
Levorphanol is approximately eight times more potent than morphine as an
analgesic in humans.
Levorphanol's increased activity results from an increase in affinity for µ
opioid receptors and its greater lipophilicity, which allows higher peak
concentrations to reach the brain. Butorphanol is a µ antagonist and a κ
agonist

13. Benzomorphans
Synthetic compounds that lack both the epoxide ring and the C ring of
morphine retain opioid activity.
Compounds having only the A, B, and D rings are named chemically as
derivatives of 6,7-benzomorphan or, using a different nomenclature
system, of 2,6-methano3-benzazocine. They are commonly referred to
simply as benzomorphans.
The only agent from this structural class that is marketed in the United
States is pentazocine, which has an agonist action on κ opioid
receptors—an effect that produces analgesia.
Pentazocine is a weak antagonist at µ receptors. The dysphoric side
effects that are produced by higher doses of pentazocine result from
actions at κ opioid receptors and also at σ (PCP) receptors.
The benzomorphan-derivative phenazocine (N-phenylethyl) is
approximately 10 times as potent as morphine as a µ agonist and is
marketed in Europe.

14. 4-Phenylpiperidines
Analgesic compounds in the 4-phenylpiperidine class may be viewed as A- and D-
ring analogues of morphine.
Meperidine proved to be a typical µ agonist, with approximately one-fourth the
potency of morphine on a weight basis. It is particularly useful in certain medical
procedures because of its short duration of action because of esterases hydrolysis
to a zwitterionic metabolite.
The 3-methyl reversed ester derivatives of meperidine, α- and β-prodine, were
available in the United States but have been removed from the market because of
their low prescription volume and their potential to undergo elimination reactions to
compounds that resemble the neurotoxic agent MPTP.

15. Anilidopiperidines
Structural modification of the 4-phenylpiperidines has led to discovery of the 4-anilidopiperidine, or the
fentanyl, group of analgesics.
Fentanyl and its derivatives are µ agonists, and they produce typical morphine-like analgesia and side
effects.
Structural variations of fentanyl that have yielded active compounds are substitution of an isosteric ring
for the phenyl group, addition of a small oxygen containing group at the 4-position of the piperidine ring,
and introduction of a methyl group onto the 3-position of the piperidine ring.

16. Diphenylheptanone
Series of open-chain compounds as potential antispasmodics.
In a manner analogous to that of meperidine, animal testing showed some of the
compounds to possess analgesic activity.
Methadone was the major drug to come from this series of compounds.
Methadone is especially useful for its oral activity and its long duration of action.
Methadone is marketed in the United States as a racemic mixture, but the (–)-
isomer possesses almost all of the analgesic activity.
Many variations on the methadone structure have been made, but little success in
finding more useful drugs in class has been achieved. Reduction of the keto and
acetylation of the resulting hydroxyl group gives the acetylmethadols.
Variations of the methadone structure have led to the discovery of the useful
antidiarrheal opioids diphenoxylate and loperamide.
Opioid activity resides in the R-enantiomer (7–50 times more potent than the S-
enantiomer).

17. Propoxyphene is metabolized via N-demethylation to form
norpropoxyphene.
Norpropoxyphene has been shown to build up in cardiac tissues and result
in naloxone-insensitive cardiotoxicity.
The weak analgesic action and potential risk to the patient have some
health practitioners advocating to remove all drugs containing
propoxyphene from the market.
Propoxyphene is an open-chain compound that was discovered by
structural variation of methadone. Propoxyphene is a weak µ opioid
agonist having only one-fifteenth the activity of morphine.
The (+)-isomer produces all of the opioid activity.

18. Flupirtine is an aminopyridine that functions as a centrally acting non- opioid analgesic that was
originally used as an analgesic for acute and chronic pain.
Flupirtine is a selective neuronal potassium channel opener that also has NMDA receptor antagonist
and GABA-A receptor modulatory properties.
Flupirtine is used as an analgesic for acute pain, in moderate-to-severe cases. Its muscle relaxant
properties make it popular for back pain and other orthopedic uses, but it is also used for migraines, in
oncology, postoperative care, and gynecology.

19. µ - Antagonists

20. All of the marketed, rigid-structured opioid analogues that have the 3-phenolic group and an N-allyl, N-
cyclopropylmethyl (N-CPM), or N-cyclobutylmethyl (N-CBM) substituent replacing the N-methyl are µ
antagonists.
Compounds behaving as µ antagonists may retain agonist activity at other opioid receptor types.
(The only exception to this rule is buprenorphine, which has an N-CPM substituent and is a potent partial
agonist (or partial antagonist) at µ receptors)
Only two compounds are pure antagonists (i.e., act as antagonists at all opioid receptors). These
compounds are the N-allyl (naloxone) and N-CPM (naltrexone) derivatives of noroxymorphone.
Naltrexone
Naloxone
Buprenorphine

21. The 14α-hydroxyl group is believed to be important for the pure antagonistic properties of these
compounds.
It is not understood how the simple change of an N-methyl to an N-allyl group can change an
opioid from a potent agonist into a potent antagonist. The answer may lie in the ability of opioid
receptor protein to effectively couple with signal transduction proteins (G proteins) when bound by
an agonist but not to couple with the G proteins when bound by an antagonist.
This explanation infers that an opioid having an N-substituent of three to four carbons in size
induces a conformational change in the receptor or blocks essential receptor areas that prevent
the interaction of the receptor and the signal transduction proteins.
Naltrexone
Naloxone
Buprenorphine

22. BUPRENORPHINE is a semisynthetic, highly lipophilic opiate derived from thebaine.
Pharmacologically, it is classified as a mixed -agonist/antagonist (a partial agonist) and a weak -
antagonist. It has a high affinity for the μ-receptors (1,000 times greater than morphine) and a slow
dissociation rate leading to its long duration of action (6–8 hours).
Buprenorphine is oxidatively metabolized by N-dealkylation by hepatic
CYP3A4 and to a lesser extent CYP2C8 to the active metabolite
norbuprenorphine.
Both the parent and major metabolite undergo glucuronidation at the
phenolic-3 position.
Minor metabolites include hydroxylation of the aromatic ring of
buprenorphine and norbuprenorphine at an unspecified site.

23. NALORPHINE also known as N-allylnormorphine, is a mixed
opioid agonist–antagonist with opioid antagonist and analgesic
properties.
It was used as an antidote to reverse opioid overdose and in a
challenge test to determine opioid dependence.

24. NALTREXONE is a pure opioid antagonist at all opioid receptor
subtypes with the highest affinity for the μ-receptor.
The CYP450 system is not involved in naltrexone metabolism.
Naltrexone is reduced to the active antagonist 6-β-naltrexol by
dihydrodiol dehydrogenase, a cytosolic enzyme.
Naltrexone has a black box warning, because it has the potential to
cause hepatocellular injury when given in excessive doses.
NALOXONE is a pure antagonist at all opioid receptor subtypes.
Very few metabolism studies on naloxone have been conducted,
although the major metabolite found in the urine is naloxone-3-
glucuronide.

25. Miscellaneous
TRAMADOL is an analgesic agent with multiple mechanisms of action. It is a
weak μ-agonist with approximately 30% of the analgesic effect antagonized by the
opioid antagonist naloxone.
Structurally, tramadol resembles codeine with the B, D, and E ring removed.
The manufacturer states that patients allergic to codeine should not receive
tramadol, because they may be at increased risk for anaphylactic reactions.
Tramadol is synthesized and marketed as the racemic mixture of two (the [2S, 3S]
[-] and the [2R, 3R] [+]) of the four possible enantiomers.
The (+) enantiomer is about 30 times more potent than the (-) enantiomer;
however, racemic tramadol shows improved tolerability.
Neurotransmitter reuptake inhibition is also responsible for some of the analgesic
activity with the (-) enantiomer primarily responsible for norepinephrine reuptake
and the (+) enantiomer responsible for inhibiting serotonin reuptake.
Like codeine, tramadol is O-demethylated via CYP2D6 to a more potent opioid
agonist having 200-fold higher affinity for the opioid receptor than the parent
compound.

26. μ- Opioid Receptor Model

28. https://www.semanticscholar.org/paper/Investigation-of-Beckett-Casy-model-3%3A-synthesis-of-Nagase-Imaide/8a4d0a284f0d72d09f723ed4b77432eeb891510b/figure/1
A representation of the original model for
the opioid receptor as proposed by Beckett
and Casy. The morphine structure would
have to rotate 180º about a vertical axis
before it could bind to the receptor site.
The model is only good for µ-selective
agents.

29. Beckett and Casy published the first such receptor drawing in 1954. They studied the configurations and
conformations of the µ agonists known at that time and proposed that all opioids could bind to the
template (receptor model) as shown.
The model presumed that nonrigid opioids (e.g., meperidine and methadone) took a shape like that of
morphine when binding to the receptor.
It soon became apparent that the most stable conformations of meperidine and methadone were not able to
be superimposed on the structure of morphine.
New compounds that could not assume the shape of morphine also were being discovered, and it became
apparent that the Beckett and Casy model could not explain the activity of all µ agonists.
Morphine and the Beckett–Casy binding model. Morphine can bind the opioid receptor site by use of
three pharmacophoric interactions; ionic, p– p (aromatic ring) interactions, and hydrogen bonding.
Furthermore, the 15–16 bond (green line) projecting in front of and to the side of the line between the
center of A ring and the basic nitrogen in morphine is proposed to fit into the cavity moiety in this model.

30. A representation of the bimodal binding model of the µ
opioid receptor as proposed by Portoghese. Different
opioid series bind to different surface areas of the same
receptor protein.
A representation of the enkephalin binding site of µ opioid
receptors . (A) An enkephalin bound to the receptor.
(B) Morphine binding the receptor by utilizing the T-subsite (i.e., the tyrosine-
binding site).
(C) A meperidine-type opioid binding the receptor by utilizing the P-subsite (i.e., the
phenylalanine-binding site).
Portoghese
Model

31. In the mid-1960s, Portoghese attempted to correlate the structures and analgesic activities of rigid and
nonrigid opioids that contained the same series of N-substituents.
He argued that if all opioids bound the receptor in the same conformation, then a substituent at a like
position on any of the compounds should fall on the same surface area of the receptor. One would expect
the same structural modification on any opioid structure to give the same type and degree of bonding
interaction and, thus, the same contribution to analgesic activity.
Portoghese found that parallel changes of the N-substituent on rigid (morphine, morphinan, or
benzomorphan) analgesic parent structures gave parallel changes in activity. This finding supported the
notion that rigid-structured opioid compounds bound to the receptor for analgesia in the same manner.
When the same test was applied to nonrigid (meperidine-like) opioid structures, however, varying the
N-substituent did not produce an activity change that paralleled that seen for the rigid-structured series.
Apparently, the N-substituents in the rigid and nonrigid opioid series were falling on different surfaces of a
receptor and, thus, making different contributions to analgesic activity.
Portoghese concluded that the rigid and nonrigid series of
compounds either were binding to different receptors or were
interacting with the same receptor by different binding modes

32. He introduced the bimodal receptor binding model as one possible explanation of the results. Later, it was
discovered that the activity of the rigid opioid compounds (Series 1) was enhanced by a 3-OH substituent
on the aromatic ring, whereas a like substituent in some nonrigid opioids (Series 2) caused a loss of
activity. Again, like substituents produced nonparallel changes in activity, indicating that the aromatic
rings in the two series were not binding to the same receptor site.
To provide an explanation for these results, the bimodal binding model was modified to incorporate the
structure of the enkephalin.
The rigid-structured opioids that benefit from the inclusion of a phenolic hydroxyl group were proposed
to bind the µ receptor in a manner equivalent to the tyrosine (Tyr1 or T-subsite) of enkephalin.
The nonrigid-structure opioids, which lose activity on introduction of a phenolic hydroxyl group into
their structure, were proposed to interact with the receptor in a manner equivalent to the phenylalanine
(Phe4 or P-subsite) of enkephalin.
The free amino group of Tyr1 occupies the anionic binding site of the receptor that is the common
binding point of both opioid series. This model closely resembles original bimodal binding proposal.

33. REFERENCE BOOKS:
1. Foye’s Principles of Medicinal Chemistry, Thomas L. Lemke, David A Williams, Lippincott
Williams & Wilkins.
2. 2. Wilson and Gisvold’s Textbook of Organic Medicinal and Pharmaceutical Chemistry, John
M. Beale, John H. Block, Lippincott Williams & Wilkins