Opioid analgesics Medicinal Chemistry-IIUC

Salahuddin Rakib,Dept of Pharmacy,IIUC. 1
Medicinal Chemistry-III
3/14/2018

• Analgesics- substance that relieves
pain
• Narcotic analgesics are drugs that
can relief pain without causing
narcosis (loss of consciousness)

Uses
• Choice of drugs for managing chronic pain as
with cancer or RA
• Used as inducing agent (fentanyl) or analgesic
supplement with General anesthetics
• They have clinical use as anti-diarrheal and
antitussive eg Loperamide and Dextromorphan
• Some opioids such as methadone and
buprenorphine are used to counter addiction of
more potent opioids such as heroin

Mechanism of action
• Opiod analgesic agonize opiod receptors µ,κ and δ
which are G-protein couples receptors. This
leads to a series of event which ultimately block
neuronal pain transmission by:
1. Inhibition of activation of voltage gated Ca+2 channels
• which depresses NT release
2. Increases K+ conductance outside the cell tocause
• hyper polarization of cell thus reducing it’s excitability
3. Inhibtion of adenyl cyclase
• (adenyl cyclase--> cAMP --> PKA --> phosphorylation of
• ion channels --> increase chances of channel opening)

Morphine
• It is a naturally occurring analgesic alkaloid extracted from
opium of poppy plant
• Modification to it’s structure has resulted more potent
compound
• Used in chronic pain management
• It is potent enough that it’s 60mg oral dose has analgesic effect
equal to parental administration
• MOA: agonizes µ receptor which depresses pain signals by
• inhibiting VGCC and prevent release of Neurotransmitters
• Opening VGPC and causing hyperporalization of nerves cells
• Inhibiting adenyl acylase

SAR
Modification to Morphine

1. Morphine has 5 Chiral centers. Only the
Levo(-) rotatory isomer is active

2. The OH group in the phenolic ring and basic Nitrogen is needed for
activity and seen in all potent µ agonist.
Activity can be preserved or enhanced by removing other rings.
Changing -OH to just –H or -OCH3 lowers activity as seen with
codeine
R= C3
substituent
Activity effect
-H 10X Decrease
-OH morphine
-OCH3
(codeine)
Decrease

Morphinans
Benzomorphine
4-Phenylpiperidines
Fig: Loss of other rings doesn’t effect analgesic activity.

3. The Nitrogen is mostly tertiary with a methyl substitution in
morphine. The size of substituent on Nitrogen dictates
potency and agonist or antagonist activity.
4. Reduction of 7,8 double bond increases activity
5. Inclusion of Hydroxyl group at 14 increases activity
6. Removal of Hydroxyl at 6 increases activity
7. Oxidation of Hydroxyl to keto group at 6 increases activity, if
there is also reduction of 7,8 double bond e.g.. hydrocodone
8. Acetylation of Hydroxyl at 6 increases activity
9. Removal of the ether linkage produces compounds called
morphinans that has increases activity.

The Beckett-Casy Hypothesis
• Positively charged nitrogen group of opioid
will form an ionic bond with anionic group
of receptor.
• In order to accomplish this “there must be
a basic nitrogen group which is then
ionized at physiological pH for form a
positively charged group (3),’ because the
positively charged group could not cross
the blood brain barrier.
• This would result in the opioids having a
pKa of around 7.8 to 8.9, which is
consistent with all opioid analgesics

The Beckett-Casy Hypothesis
• The hypothesis also proposes van der Waals
interaction between the aromatic ring and a
hydrophobic region of the binding site
• This suggests a close spatial relationship between
the aromatic ring of the opioid and the surface of
the binding site
• The hypothesis also suggests hydrogen bonding with
the phenol group of the opioid and the receptor binding
site
• It also proposes that the receptor possesses a unique
structural feature that allows the ethylene bridge of the
opioid to snugly fit into the binding site and in doing so
properly aligning the rest of the molecule with the
associated binding regions.

Drawbacks with the Beckett-Casy hypothesis
* Ethylene bridge is not important in some analgesics (fentanyl)
* No account for extra binding regions found by extension
* Does not explain different SAR results (e.g. meperidine vs morphine)
* Does not explain mixed antagonist/agonist properties

Multiple Analgesic Receptors
* Three different analgesic receptors (mu, kappa and delta)
* Binding sites for all three receptors contain ionic, hydrogen bonding and hydrophobic
regions as proposed by Beckett-Casy
* Activation of all three produce analgesia, but differ in other effects
* All three interact with morphine
* Potential to target drugs selectively

Mu Receptor (m)
* Morphine binds strongly
* Activation produces analgesia plus side effects
(respiratory depression, euphoria, addiction)
* G-Protein coupled receptor
* m-Receptor subtypes identified which may allow separation of analgesia from
side effects
* m-Receptors related to all sources of pain stimuli

Kappa Receptor (k)
* Morphine binds less strongly
* Activation produces analgesia plus sedation
* Insignificant side effects
* Potential target for safe analgesics (compounds acting as agonists at k, antagonists at m
and no activity at the d receptor).
* G-Protein-coupled receptor
* k Receptors related to non-thermal pain induced stimuli

Delta Receptor (d)
* Morphine binds strongly
* Receptor for enkephalins
* Activation produces analgesia plus some side effects
* G-Protein-linked receptor
* d receptors related to pain induced stimuli from all sources
Sigma Receptor (s)
* Activated by some opoid analgesics (e.g. nalorphine)
* Non-analgesic, non-opoid receptor
* Activation produces hallucinogenic effects
* Thought to be responsible for effects of phencyclidine (PCP) (Angel Dust)

Receptor mechanisms
All receptors in the body are situated on the surface of cells and act as
communication centres for the various messages being sent from one part of the
body to another. The message may be sent through nerves or via hormones, but
ultimately the message has to be delivered from one cell to another by a chemical
messenger.
This chemical messenger has to 'dock' with the receptor which is waiting for it.
When it does so, it forces the receptor to change shape. This change in shape of
the receptor molecule may force a change in the shape of some neighbouring
protein or perhaps an ion channel, resulting in an alteration of ion flows in and
out of the cell. Such effects will ultimately have a biological effect, dependent on
the cells affected.

The mu receptor (µ)
Morphine binds to the (µ) receptor and induces a change in shape. This change
in conformation opens up an ion channel in the cell membrane and as a result,
potassium ions can flow out of the cell. This flow hyperpolarizes the membrane
potential and makes it more difficult for an active potential to be reached.
Therefore, the frequency of action potential firing is decreased, which results in
a decrease in neurone excitability. This increase in potassium permeability has
an indirect effect, since it also decreasesthe influx of calcium ions into the
nerve terminal and this in turn reduces neurotransmitter release. Both effects,
therefore, 'shut down' the nerve and block the pain messages. Unfortunately,
this receptor is also associated with the hazardous side-effects of narcotic
analgesics Salahuddin Rakib,Dept of Pharmacy,IIUC. 19

The kappa receptor (K)
The K receptor is directly associated with a calcium channel (Fig. 12.42).
When an agonist binds to the K receptor, the receptor changes
conformation and the calcium channel (normally open when the nerve is
firing and passing on pain messages) is closed. Calcium is required for the
production of the nerves neurotransmitters and therefore the nerve is shut
down and cannot pass on pain messages.
The nerves affected by the K mechanism are those related to pain induced by
nonthermal stimuli. This is not the case with the JJL receptor where all pain
messages are inhibited. This suggests a different distribution of K receptors
from JJL receptors Salahuddin Rakib,Dept of Pharmacy,IIUC. 20

The delta receptor (d)
There are no ion channels involved (Fig. 12.43). The substrate molecule binds to the A
receptor and, in some way, the message is transmitted through the cell membrane to
a second membrane-bound protein. This protein then acts as an enzyme for the
formation of cyclic AMP (Fig. 12.44). Normally, theactive site is open when the nerve
is receiving pain
messages, such that cyclic AMP acts as a secondary messenger and passes on the pain
messages. However, when the A receptor is activated it probably changes shape and
as a result leads to a change in shape of the cyclase enzyme to close down the
phosphate (cAMP).
active site by which it can make cyclic AMP.

Sigma Receptor (s)
This receptor is not an analgesic receptor, but we have seen that it can be
activated by certain opiate molecules such as nalorphine. When activated, it
produces hallucinogenic effects. The a receptor may be the one associated with
the hallucinogenic and psychotomimetic effects of phencyclidine (PCP), otherwise
known as 'angel dust

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Opioid analgesics Medicinal Chemistry-IIUC

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