00 Med Chem, topic 4, 5, 8 for posting.ppt

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B = agonist

E = partial agonist

A = restingC = antagonist(background activity)

© Oxford University Press, 2013 1

D = inverse agonist

Equilibrium between active and inactive forms

HO

N

How?HO

N

Morphine is a pain medication of the opiate type which is found naturally in a number of plants and animals. It acts directly on the central nervous system (CNS) to decrease the feeling of pain. It can be taken for both acute pain and chronic pain.

HO

Mittens and Louise

O

Tramadol (prodrug), sold under the brandname Ultram, is an opioid pain medication used to treat moderate to moderately severe pain. When taken as an immediate-release oral formulation, the onset of pain relief usually occurs within about an hour. It has two different mechanisms. First, it works by binding to the µ-opioid receptor. Second, it inhibits the reuptake of serotonin and

HOprodrug activedrug


O

HO

H

NCH3

Morphine

, pnorepinephrine. It is often combined with paracetamol (acetaminophen) as this is known to improve the efficacy of tramadol in relieving pain.

Acetaminophen (Tylenol) - foremost cause of acute liver failure in the Western world and accounts for most drug overdoses in the United States

HN

OHO

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Opioid receptors are a group of inhibitory G protein-coupled receptors with opioids as ligands. The endogenous opioids are dynorphins, enkephalins, endorphins, endomorphins and nociceptin. The opioid receptors are distributed widely in the brain, and are also found in the spinal cord and digestive tract. Brain opioid peptide systems are known to play an important role in motivation, emotion, attachment behaviour, the response to stress and pain, and the control of food intake.

These are allTM-7 G coupled receptor proteins

The opioid receptor family originated from two duplication events of a single ancestral opioid receptor early in vertebrate evolution. Phylogenetic analysis demonstrates that the family of opioid receptors was already present at the origin of jawed vertebrates over 450 million years ago. In humans, this double tetraploidization event resulted in the receptor genes being located on chromosomes 1, 6, 8, and 20. Tetraploidization events often result in the loss of one or more of the duplicated genes, but in this case nearly all species retain all of the opioid receptors indicating


case, nearly all species retain all of the opioid receptors, indicatingimportant and specific function. The receptor families delta, kappa, and mu demonstrate 55–58% identity to one another, and a 48–49% homology to the nociceptin receptor.

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Dynorphin A is a form of dynorphin and an endogenous opioid peptide with the amino acid sequence:

Tyr-Gly-Gly-Phe-Leu-Arg-Arg-Ile-Arg-Pro-Lys-Leu-Lys.

N

H3CO

O

CH3

cocaine

Dynorphin A contains a high proportion of basic amino acid residues, 29.4% basic residues, as well as 41.2% hydrophobic residues. The dynorphins are found widely distributed in the CNS. Their storage vesicles are larger and more dense and a stronger and prolonged stimulus is needed to cause the large vesicles to release their contents into the synaptic cleft.

The dynorphins are found to be extraordinarily potent opioid peptides (called dynorphin (from the

O

H O

cocaine


Greek dynamis=power) to describe its potency.

Dynorphins exert their effects primarily through the -opioid receptors (KOR), a G-protein-coupled receptor. Two subtypes of KORs have been identified: K1 and K2. Although KOR is the primary receptor for all dynorphins, the peptides do have some affinity for the µ-opioid receptor (MOR), -opioid receptor (DOR),and the N-methyl-D-aspartic acid (NMDA)-type glutamate receptor.

Dynorphins have been shown to be an important part of the process of cocaine addiction. Although a single exposure to cocaine does not affect brain dynorphin levels, repeated exposures to the drug increases dynorphin concentrations in the striatum and substantia nigra in rats.

An enkephalin is a pentapeptide involved in regulating nociception (extreme pain sensations: smashing your toe, cutting yourself, burning yourself, etc.) in the body. The enkephalins are termed endogenous ligands, as they are internally derived and bind to the body's opioid receptors. Two forms of enkephalin were discovered, one containing leucine ("leu"), and the other containing methionine ("met"). Both are products of the proenkephalin gene.

Met-enkephalin is Tyr-Gly-Gly-Phe-Met.Leu-enkephalin has Tyr-Gly-Gly-Phe-Leu.

© Oxford University Press, 2013 6Met-enkephalin

Morphine

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E d hi ( d f " d hi " d i id

α-endorphin

Endorphins (contracted from "endogenous morphine"are endogenous opioid neuropeptides and peptide hormones in humans and other animals. They are produced by the central nervous system and the pituitary gland. The term "endorphins" consists of two parts: endo- and -orphin; these are short forms of the words endogenous and morphine, intended to mean "a morphine-like substance originating from within the body". The class of endorphin compounds includes -endorphin and several other related peptides. The principal function of endorphins is to inhibit the transmission of pain signals; they may also produce a feeling of euphoria very similar to that produced by other opioids.

Endorphin is an endogenous opioid peptide with an amino acid sequence:


-Endorphin is an endogenous opioid peptide with an amino acid sequence:

Tyr-Gly-Gly-Phe-Met-Thr-Ser-Glu-Lys-Ser-Gln-Thr-Pro-Leu-Val-Thr.

Endomorphins are a group of endogenous opioid peptides consisting of

Tyr Pro Trp Phe

Tyr Gly Phe

NH3

NH3Phe

endomorphin-1

endomorphin-2

Endomorphins are tetrapeptides with the highest known affinity and selectivity for the µ-opioid receptor. Endomorphin-1 may regulate sedative and arousal behaviors. It is assumed that endomorphins are the cleavage products of a larger precursor, but this polypeptide or protein has not yet been identified.

In rats similarly potent dosages of synthetic endomorphin and morphine produced comparable amounts of pain relief. However, motor skills and breathing were significantly impaired in those receiving morphine, while the endomorphin rats did not. The morphine rats spent more time in the compartment where they had received morphine, while the endomorphin rats did not. Only the morphine rats made efforts to


secure further doses of the drug. Endomorphin did not activate spinal glial cells, anestablished morphine effect that helps to build tolerance of the drug.

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Nociceptin is a 17-amino acid neuropeptide, is the endogenous ligand for the nociceptin receptor and acts on numerous brain activities such as pain sensation and fear learning. Nociceptin is the first example of reverse pharmacology; the NOP receptor was discovered before the endogenous ligand which was discovered by two separate groups in 1995.

Nociceptin and its receptor are widely distributed throughout the CNS.

Unlike morphine and other opioids that are used to alleviate pain, nociceptin's role can counteract analgesia, thus acting as an anti-opioid. Blocking the nociceptin receptor can lead to an increased pain threshold and a decreased tolerance development to analgesic opioids and may help lower risks of addiction of many pain relievers that are currently used.

Animals studies suggest that nociceptin plays plays a part in both anxiety and depression. It appears that nociceptin inhibits anxiety but also seems to perpetuate depression


inhibits anxiety, but also seems to perpetuate depression.

Noiceptin been found to play both positive and negative roles in both learning and memory. It is implicated in control of the cardiovascular system in blood pressure and heart rate that vary by species. In the renal system, nociceptin plays a role in water balance, electrolyte balance, and arterial blood pressure regulation.

In the gut, nociceptin has been found to have varying effects on the stomach and the intestines. It also stimulates increased consumption of food. And finally, studies have shown that nociceptin may have an effect as an anti-epileptic drug component.

The -opioid receptor (KOR) is a protein that in humans is encoded by the OPRK1 gene. The KOR is one of four related receptors that bind opioid-like compounds in the brain and are responsible for mediating the effects of these compounds. These effectsthe effects of these compounds. These effectsinclude altering nociception, consciousness, motor control, and mood.

The KOR binds the opioid peptide dynorphin as the primary endogenous ligand. In addition to dynorphin, a variety of natural alkaloids, terpenes and other synthetic ligands bind to the receptor. The KOR may provide a natural addiction control mechanism, and therefore, drugs that act as agonists and increase activation of this receptor may have therapeutic potential in the


act as agonists and increase activation of this receptor may have therapeutic potential in the treatment of addiction.

There is evidence that distribution and/or function of this receptor may differ between sexes.

KOR agonists are potent analgesics, and have been employed clinically in the treatment of pain. However, KOR agonists also produce side effects such as dysphoria (profound state of unease), hallucinations, and dissociation, which has limited their clinical usefulness.

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The µ-opioid receptors (MOR) are a class of opioid receptors with a high affinity for enkephalins and beta-endorphin. The prototypical µ-opioid receptor agonist is morphine, the primary psychoactive alkaloid in opium.

Activation of the µ-opioid receptor by an agonist such as morphine causes analgesia, sedation, slightly reduced blood pressure, itching, nausea, euphoria, decreased respiration, miosis (constricted pupils), and decreased bowel motility often leading to constipation. Some ofbowel motility often leading to constipation. Some ofthese effects, such as analgesia, sedation, euphoria, itching and decreased respiration, tend to lessen with continued use as tolerance develops. Reduced bowel motility tend to persist; little tolerance develops.

Opioid overdoses kill through apnea and fatal hypoxia, often caused by combination with ethanol, benzodiazepines, or barbiturates. Substantial tolerance to respiratory depression develops quickly, and tolerant individuals can withstand larger doses. However tolerance to respiratory depression is lost


naloxone

O

HO

O

OH

N

However, tolerance to respiratory depression is lostjust as quickly during withdrawal. Many overdoses occur in people who misuse their medication after being in withdrawal long enough to lose the tolerance to respiratory depression. Less commonly, massive overdoses have been known to cause circulatory collapse.

Opioid overdoses can be rapidly reversed through the use of opioid antagonists, naloxone being the most widely used example.

The -opioid receptor, also known as delta opioid receptor or simply delta receptor, abbreviated DOR, is a 7-transmembrane G-protein coupled receptor, that has enkephalins as its endogenous ligands. The regions of the brain where the -opioid receptor is largely expressed vary from species model to species model. In humans, the -opioid receptor is most heavily expressed in the basal ganglia and neocortical regions of the brain; the basal ganglia, which is heavily GABA populated, h b li k d j d i di d ihas been linked to major depressive disorder, suggestinga possible role for the -opioid receptor in mood modulation.

It is suggested that the pain modulated by the -opioid receptor and that modulated by the -opioid receptor are distinct types, with the assertion that DOR modulates the nociception of chronic pain, while MOR modulates acute pain.


A showing of selective delta opioid ligands. Blue represents a common phenolic moiety, yellow a basic nitrogen, and red a diethyl amide moiety which isn't set in stone, but rather a bulky region that fits into a hydrophobic pocket

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Addiction, dependence, sensitization and tolerance

• addiction – a brain disorder characterized by compulsive engagement in rewardingstimuli despite adverse consequences

• addictive behavior a behavior that is both rewarding and reinforcing• addictive behavior – a behavior that is both rewarding and reinforcing

• addictive drug – a drug that is both rewarding and reinforcing

• sensitization – an amplified response to a stimulus resulting from repeated exposure to it

• tolerance (desensitization) – the diminishing effect of a drug resulting from repeated administration at a given dose, higher levels of a drug are needed to get


p g , g g gthe same biological response, if a drug is withdrawn, distressing symptoms may occur (dependency)

Desensitization and Sensitization

Desensitization• Receptors become desensititized on long term exposure to agonists• Prolonged binding of agonist leads to phosphorylation of receptor • Phosphorylated receptor changes shape and is inactivated• Dephosphorylation occurs once agonist departs

Receptor

O O2C

1

H Ion channel(closed)

AgonistNH3

Receptor

O

H

AgonistNH3

O2C

•Induced fit alters protein shape

•Opens ion channel++


Receptor

O

H

AgonistP

O2C

NH3

•Possibly phosphorylationalters shape

•Ion channel closes•Desensitization

+

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Sensitization

• Receptors become sensititized on long term exposure to antagonists• Cell synthesizes more receptors to compensate for blocked receptors• Cells become more sensitive to natural messenger

C lt i t l d d d• Can result in tolerance and dependence• Increased doses of antagonist may be required to achieve same effect (tolerance)• Cells can become supersensitive to normal neurotransmitter • Can cause withdrawal symptoms when an antagonist is withdrawn • Can lead to dependence


Electrical or chemical stimulation of the rat hippocampus causes strengthening of synaptic signals, a process known as long-term potentiation (LTP), which is a potential mechanism underlying memory and learning in the brain.

In "kindling", repeated stimulation of hippocampal or amygdaloid neurons (from repeated withdrawal episodes) in the limbic system eventually leads to seizures in laboratory animals. After sensitization, very little stimulation may be required to produce seizures. Thus, kindling has been suggested as a model for

l l b il i h h i l i f i itemporal lobe epilepsy in humans, where stimulation of a repetitive type(flickering lights for instance) can cause epileptic seizures. Often, people suffering from temporal lobe epilepsy report symptoms of negative effects such as anxiety and depression that might result from limbic dysfunction.


The limbic system supports a variety of functions including emotion, behavior, motivation, long-term memory, and olfaction. Emotional life is largely housed in the limbic system, and it has a great deal to do with the formation of memories.

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Sensitization

Neurotransmitter

Normal response

Antagonist

Receptorsynthesis

No response

ResponseReceptorsynthesis

Sensitization

No response

© Oxford University Press, 2013

StopantagonistExcess response No response

Increaseantagonist

Tolerance

Dependence

No response

17

Design of an antagonist for the estrogen receptor

Action of the estrogen receptor

H12

Binding site

AF-2 regions

Coactivator Coactivator

Estradiol

Estrogenreceptor

Dimerisation &exposure of AF-2 regions

Nucleartranscription

factor

DNA

Transcription

OHCH3

H

OHCH3

H


H

H

H

HO

H

H

H

H

O

CH3

Estradiol / EstrogenTestosterone

How?

18

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Binding interactions for estradiol


His 524

O

Me OH

H

H H

H

H

H2O

Glu353

Arg394

Hydrophic skeleton


• Phenol and alcohol of estradiol are important binding groups• Binding site is spacious and hydrophobic• Phenol group of estradiol is positioned in narrow slot• Orientates rest of molecule• Acts as agonist

Note:

Estradiol

19

Binding interactions for raloxifene


Asp351

N H

OH

S

O

O

Raloxifene

His 524

O

Glu353

Arg394

N

H

Side chain


Note: Raloxifene is an antagonist (anticancer agent)Phenol groups mimic phenol and alcohol of estradiolInteraction with Asp-351 is important for antagonist activitySide chain prevents receptor helix H12 folding over as lidAF-2 binding region not revealedCo-activator cannot bind

Raloxifene

20

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Tamoxifen - antagonist for estrogen receptor

Design of an antagonist for the estrogen receptor O H

O

H

H

HH

N

H

Me Estradiol

O

T if

O

H

O H

if b li

Me

in the body


Tamoxifen(antagonist)

Tamoxifen metabolite(agonist)

Tamoxifen is currently used for the treatment of both early and advanced ER+ (estrogen receptor positive) breast cancer in pre- and post-menopausal women. Additionally, it is the most common hormone treatment for male breast cancer. It is also approved by the FDA for the prevention of breast cancer in women at high risk of developing the disease. The use of tamoxifen is recommended for 10 years. A large 2006 STAR clinical study concluded that raloxifene is equally effective in reducing the incidence of breast cancer, but after an average 4-year follow-up there were 36% fewer uterine cancers and 29% fewer blood clots in women taking raloxifene than in women taking tamoxifen.

L = radiolabelled compound


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00 Med Chem, topic 4, 5, 8 for posting.ppt

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