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 Pharmaceutical Chemistry - THE BRAIN

Topics to Cover:

1. Narcotic Analgesics Part 1 - February 22

2. Narcotic Analgesics Part 2 - February 24
3. Serotonergic Neurochemistry/Depression - February 28
4. Pharmacotherapy of Anxiety and Depression - March 3
5. Pharmacotherapy of Psychosis - March 14
6. Preview of Antiepileptic Agents - Coming Soon - March 15
 01
Narcotic
Analgesics Part 1
and Part 2
 PAIN:
An unpleasant sensory and emotional experience associated with actual or
potential tissue damage, or described in terms of such damage

NEUROPATHIC
NOCICEPTIVE ★ Caused by nerve damage or disease that affects the
nervous system (diabetes, cancer, vitamin B deficiency,
★ Caused by tissue damage (cut, burn, HIV)
inflammation) ★ Associated with abnormal sensation
★ Peripheral nerve transfers the signal to the ★ Peripheral neuropathic pain: diabetes, herpes zoster
brain via the spinal cord infection, HIV-related neuropathies, nutritional
deficiencies, cancer
★ Pain signals are modulated throughout the ★ Central neuropathic pain: spinal cord injury, multiple
pathways sclerosis, stroke
★ ACUTE ★ CHRONIC
Opioid Peptide Receptors
● GCPR (G-coupled protein receptors) that are mainly distributed in the CNS
● 7 transmembrane domains
○ This means it crosses the cell membrane 7 times
● There are 4 types of opioid receptors
○ Mu-opioid
○ Kappa-opioid
○ Delta-opioid
○ Nociceptin receptor

Note: mu, kappa, and delta receptors → main fxn is to regulate pain

Note: nociceptin receptors → think about anxiety and depression as well

Structure Activity Relationship: the Phenolic OH
● The phenolic OH is the hydroxyl group circled in red
● This OH group is crucial for analgesic activity
○ As binding affinity to MOR increases, analgesic activity increases
■ Therefore masking this, by replacing the H with bigger groups
DECREASES ANALGESIC ACTIVITY
● Comparing morphine and codeine
○ Morphine has a H attached to the O
○ Codeine has CH3 attached to the O
○ Binding affinity for codeine is only 0.1% that of morphine!
○ Analgesic effect of codeine is 20% that of morphine.
SAR continued
● The 6-alcoholic OH is NOT important for analgesic activity
○ Therefore, masking the 6-alcoholic OH does not decrease analgesic
activity

● The “E Ring” (particularly the basic Nitrogen) is crucial for activity

○ Without the E ring, there is a complete loss of activity

● However, loss of the B, C, or D ring is NOT essential for activity

MOR Agonists
● Fentanyl
○ Full MOR agonist
○ 50-100x MORE potent than morphine
■ Fentanyl is associated with increasing rates of overdose deaths
● Buprenorphine
○ Partial MOR agonist (activates the MOR at a lower degree than a full MOR
agonist, such as morphine)
■ Lower risk of respiratory depression
■ Used in treatment of opioid addiciton
MOR Antagonists
● Naloxone
○ Competitive MOR Antagonist
■ no opioid analgesic effect and adverse effects
■ Used to treat acute opioid overdoses (ex: Narcan nasal spray)
■ *cannot reverse fentanyl OD*
● Naltrexone
○ Competitive MOR Antagonist
■ CANNOT treat acute opioid overdoses

Naloxone acts quickly but does not last long (~1hr); naltrexone lasts for a day.
 Top Hat
Question
1-4
 02
Serotonergic
Neurochemistry
and Depression
Serotonin (5‐hydroxytryptamine, 5‐HT)
● Biosynthesis: serotonin is formed from the AA, tryptophan, in 2 steps

● Metabolism
○ Major metabolite = 5‐hydroindole acetic acid (5‐HIAA)
■ Monoamine oxidase (removes the amine) and aldehyde
dehydrogenase (converts -CHO into -COOH) are the 2 enzymes that
convert 5-HT into 5-HIAA
○ Minor metabolites = 5-hydroxytryptophol and Melatonin
Serotonin (5‐hydroxytryptamine, 5‐HT)
● Biological functions - its primary functions are performed in the BRAIN
○ Serotonin’s functions include: sleep, cognition, sensory perception, motor
activity, temperature regulation, nociception, mood, appetite, sexual
behavior, and hormone secretion.
● An imbalance (deficient) in serotonin levels may lead to depression!!
● There are 14 serotonin receptor subtypes
○ All of which are GCPRs
■ EXCEPT for 5-HT3 (5-HT3 is a ligand-gated ion channel)
○ 5‐HT1B and 5‐HT1D are auto-receptors (located on presynaptic cell &
regulate 5‐HT release)
○ 5‐HT1A and 5‐HT2A functions include: anxiety and depression
Clinical significance by affecting 5‐HT Signaling
● Selective serotonin reuptake inhibitors (SSRI), Serotonin norepinephrine
reuptake inhibitor (SNRI), and tricyclic antidepressants (TCA)
○ Inhibit 5-HT transporter (SERT)
■ Inhibition of SERT → increases levels of 5-HT in the synapse

● Monoamine oxidase inhibitors (MAOi): inhibits monoamine oxidase, an enzyme

involved in serotonin metabolism
○ Use of MAOi prevents 5-HT metabolism → increases levels on 5-HT

● Partial agonists can act on 5-HT receptors on the postsynaptic neuron

○ Ex: Buspirone, Tegaserod
 Top Hat
Question
5 and 6
 03
Pharmacotherapy
Anxiety and
Depression
SSRIs
● First-line treatment for depression because they are effective and have less
side effects than older antidepressants (such as TCAs and MAOi)
○ Examples: citalopram, escitalopram, sertraline, fluoxetine, and
fluvoxamine

● SSRIs block reuptake of 5HT and enhance and prolong serotonergic

neurotransmission
● BBW: Antidepressants may increase the risk of suicide in patients under 25
Citalopram - racemic mixture with 2 isoforms (R and S)
★ S-Citalopram (Escitalopram) is most selective as it is a pure enantiomer of the S
isomer - S is much more active
★ Used to treat major depressive disorder
★ Side Effects:
○ Sexual dysfunction
○ Abnormal heart rhythm
○ INCREASED RISK OF SUICIDE < 25 years old
○ Discontinuation symptoms - electric shock sensations, dizziness, acute
depression
○ Overdose has FLU-LIKE symptoms - sedation, dizziness, tremor - DEATHS
HAVE OCCURED
 RACEMIC VERSUS PURE Chiral
center

Citalopram Escitalopram

Racemic mixture of R and S enantiomers Pure S enantiomer

Metabolism and Drug Interactions
Metabolized mainly by the liver - 80%
cleared by liver 20% cleared by kidney

May increase risk of bleeding with inactive

inactive
NSAIDS, warfarin, and other blood oxidized
thinners

Risk of serotonin syndrome if taken

with St. John’s wort or other SSRIs
Sertraline
★ Most prescribed psychiatric medicine in the US in 2016
○ Used to treat major depressive disorder, obsessive compulsive disorder,
posttraumatic stress disorder, panic disorder, social anxiety disorder, and
more
★ SIDE EFFECTS:
○ Sexual dysfunction
○ Abnormal heart rhythm
○ Higher rate of psychiatric side effects and diarrhea
○ INCREASED RISK OF SUICIDE <25 years old
○ Discontinuation symptoms
 demethylation
Major metabolite
Norsertraline
Less active than sertraline
(BUT STILL ACTIVE)

Metabolism of Sertraline
 FluvoxAmine
★ Approved to treat obsessive
compulsive disorder - FIRST
★ Has E configuration (E -
trans, Z - cis) only E (trans) Double bond E isomer

is on the market
★ More GI side effects than
other SSRIs
 Chiral center
Removed
Fluoxetine
★ Sold as a racemic mixture
★ Metabolized in the liver by CYP2D6
★ Major metabolite is the demethylated-product, norfluoxetine
★ Both fluoxetine and norfluoxetine inhibit CYP2D6
★ Fluoxetine has an extremely long half-life (1-3 DAYS)
★ Less common to develop discontinuation syndrome due to long half life
★ KNOW:
○ Metabolite has about the same activity as the initial drug
○ Fluoxetine inhibits activity of enzyme used to metabolize it - this
slows/stops drug metabolism causing the drug to stay in the blood
longer
SNRIs
● Inhibit SERT and NET → cause enhanced serotonergic or noradrenergic
neurotransmission
○ Used for the treatment of depression, anxiety disorders, pain, etc.
● Examples: Venlafaxine, Desvenlafaxine, Duloxetine, Milnacipran, and
Levomilnacipran

● BBW: Antidepressants may increase the risk of suicide in patients under 25

Venlafaxine:

● SNRI antidepressant — 2nd line treatment for depression

○ SSRIs are 1st line tx
● Metabolized by CYP2D6 in the liver Venlafaxine
○ Major metabolite = desvenlafaxine
■ This metabolite is as potent as venlafaxine
● Note: Patients taking venlafaxine had significantly higher risk of completed suicide than
the ones taking SSRI

Duloxetine: Duloxetine

● Another SNRI antidepressant

● The S-enantiomer (Duloxetine) inhibits SERT two times more than the R-enantiomer
● Metabolized by CYP26 (like venlafaxine) and CYP1A2
○ Major metabolites are INACTIVE
Tricyclic Antidepressants (TCAs)
● Contain three rings (benzene, 7-membered ring, and benzene)
○ Also contain: 3-Carbon linker and Basic N
● Older antidepressants, discovered in the 1950s
● MOA: act primarily as SNRIs by blocking SERT and NET
○ However, they lack selectivity at SERT and NET
○ Examples:
■ Amitriptyline, imipramine, doxepin (tertiary amines)
■ Nortriptyline, desipramine (secondary amines)
● Imipramine Metabolism:
○ Metabolized by CYP2C19, CYP1A2 and CYP3A4 into desmethylimipramine
○ Metabolized by CYP2D6 into 2-hydroxy-imipramine
Serotonin Antagonists and Reuptake inhibitor
(SARIs)
● These drugs antagonize the 5HT2A receptor and weakly inhibit 5-HT
reuptake
● Examples:
○ Trazodone: potent 5HT2A antagonist, weak SERT inhibitor
○ Nefazodone: potent 5HT2A antagonist, weak SERT inhibitor
● Trazodone Metabolism:
○ Metabolized by CYP3A4, in the liver
○ Has 4 major metabolites
■ mCPP = one of trazodone’s metabolites
● mCPP may contribute trazodone’s SE profile: blurred
vision, dizziness, nausea, dry mouth, headache,
somnolence, and fatigue
● mCPP is metabolized by CYP2D6 into para-mCPP
Serotonin modulators and stimulators (SMSs)
● Simultaneously modulate one or more serotonin receptors

AND inhibit the reuptake of serotonin

● Examples:
○ Vilazodone: inhibits SERT + Partial agonist at 5‐HT1A + inhibit NET and
DAT
○ Vortioxetine: inhibits SERT + Agonist at 5‐HT1A + Antagonist at 5‐HT1D,
5‐HT3, 5‐HT7
5‐HT1 receptor agonists —Azapirones
● Used as add‐ons to other antidepressant, such as SSRIs
○ 5-HT1 receptor agonists are LESS EFFECTIVE than SSRIs
■ Examples:
● Buspirone, Gepirone, and Ipsapirone
● Metabolized in the liver
○ common metabolite is pyrimidinylpiperazine

Buspirone
 Tranylcypromine
MAOIs
● Inhibiting MAO inhibits the body’s capacity to metabolize
endogenous monoamines NE and 5HT, but also exogenous biogenic
amines (ex: tyramine)
Phenelzine
○ Examples:
■ Tranylcypromine and Phenelzine: non-selective and
irreversible
■ Selegiline: selective and irreversible inhibitor of MAOB
● MAOIs and Tyramine:
○ Use of MAOI → increases BA of dietary tyramine → induces NE
release → increases BP
● As effective as TCAs, however they are rarely used due to:
○ Toxicity and DDIs
 Top Hat
Question
7-10
 04
Pharmacotherapy
of Psychosis
● Psychosis
○ Symptom of mental illness - distorted or Psychosis and the Dopamine
nonexistent sense of reality Hypothesis
○ Could include major depression or mania with
psychotic features
○
● Dopamine hypothesis:
○ Distrubed AND hyperactive dopaminergic signal
transduction, particularly prefrontal
hyperdopaminergia results in schizophrenia
symptoms
○ The dopamine hypothesis resulted in the
development of typical (1st generation)
antipsychotic agents AKA D2 antagonists
(because they stop the hyperactive dopaminergic
signal transduction!)
○ D2 antagonists have a HIGHER risk of EPSx
Atypical AKA 2nd Generation Antipsychotics
● These drugs are antagonists at 5-HT2A and D2, antagonists at
5-HT2A and partial agonist at D2
● These drugs have a LOWER potential for extrapyramidal (EPS)
side effects
● These drugs have a HIGHER concern for metabolic
dysregulation such as weight gain and T2DM
 Top Hat
Question
11
Potency of 1st Potency of 2nd
Generation Generation
Haloperidol has the Clozapine was the first
highest binding affinity, atypical antipsychotic and
and thus the highest it targets both the D2 and
potency. 5-HT2A receptors
 Representative
Structures Benzodiazepine

PheNothiaziNe

space
aryl
ThioXanthene

terminus
piperazine

Long-chain arylpiperazine

First Generation Second Generation

 Top Hat
Question
12
 05
Preview:
Antiepileptic
Agents
 Types of Seizures - excessive neuron firing
Focal Seizure: one
area of the brain

Examples: simple
focal seizure,
complex focal
seizure
Generalized Seizure :
both sides of the brain
A secondary generalized
Examples: tonic-clonic
seizure begins as a focal
and absence seizure
seizure and is followed by
a generalized seizure
 Anti-seizure Drugs

Voltage-Dependent Enhance GABA activity

Sodium Channels
Phenytoin/Fosphenytoin Benzodiazepines

Carbamazepine Barbiturates

Lamotrigine, Topiramate, GABA analogs

Valproic Acid
 Top Hat
Question
13
GOOD LUCK!
Make sure you review Dr. Li’s TopHat questions
THANKS
Do you have any questions?

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