Med Chem II Final Exam - Li

drugs used for mild-to-moderate pain (step 1)

- nonopioids such as acetaminophen or NSAIDs

drugs used for mild-to-moderate pain uncontrolled after step 1 (step 2)

- short-acting opioid as required +/- nonopioid

- morphine, oxycodone, or hydromorphone should be added to acetaminophen or NSAID

moderate-to-severe pain or pain uncontrolled after step 2 (step 3)

- sustained-release/long-acting opioid or continuous infusion short-acting opioid as required +/- nonopioid

- sustained-release morphine, oxycodone, or hydromorphone or transdermal fentanyl as indicated

metabolism of opioids

- first pass metabolism in liver

- major metabolic reactions include phase II metabolism and glucuronidation (M6G active and M3G inactive metabolites)

- phase I reaction includes demethylation (non-morphine, less-active metabolites)

adverse effects of opioids

- tolerance and dependence

- abuse and addiction

- respiratory depression

- constipation

respiratory depression with opioids

- MOR expressed on respiratory neurons in brainstem regulates breathing

- activating MOR depresses ventilation

- life threatening

constipation with opioids

- MOR in GI tract regulates GI motility

- activating MOR in GI delays transit and stimulates non-propulsive motility, segmentation, and tone

SAR of 3-phenolic OH in opioids

- phenolic OH is crucial for activity

- masking the phenolic OH loses binding affinity and dramatically decreases analgesic activity

- as affinity to MOR decreases, analgesic activity decreases

SAR of 6-alcoholic OH in opioids

- alcoholic OH is not important for activity

- masking 6-OH does not decrease analgesic activity, it often increases activity due to increased hydrophobicity

SAR of ring E in opioids

- ring E, particularly the basic N, is crucial for activity

- removing E results in complete loss of activity

SAR of ring D in opioids

- ring D is not essential for activity

- activity retains

SAR of ring C in opioids

- ring C is not essential for activity

- metazocine is as potent as morphine

SAR of ring B in opioids

- ring B is not essential for activity

- pethidine has 20% of the activity of morphine

morphine structure and activity properties

- 5 fused ring system (increases selectivity and affinity to receptor)

- rigid T shape (increases brain penetration)

- 2 hydroxyl groups (phenolic OH is crucial for activity)

- 5 chiral centers (crucial for activity but only (-) is active)

- a basic tertiary amine (basic N (alkaloid) is crucial for activity)

codeine

- morphine opioid analgesic that is less potent than morphine and is used in pain and cough

- prodrug of morphine

- binding affinity is only 0.1% that of morphine and resulting analgesic effect is 20% that of morphine

- metabolized by CYP2D6 in the liver into morphine to produce analgesia (O-demethylation and UGTs)

- CYP2D6 is highly polymorphic and considerable variation exists in the efficiency and amount of CYP2D6 enzyme produced between individuals

- individual patient's response to codeine varies from no effect to high sensitivity

hydromorphone

- morphine opioid analgesic that is more potent than morphine and is used in pain

buprenorphine

- morphine opioid analgesic that is a partial agonist and is used in pain and withdrawal symptoms

- occupies MOR but activates MOR at a lower efficacy than morphine and has a "ceiling" on analgesia and side effects

- lower risk of respiratory depression than a full agonist morphine

- tolerance development with chronic use

- low-dose injection and transdermal patches for moderate-severe chronic pain

- high-dose SL tablets also containing naloxone are used for the treatment of opioid addictions

- medication for opioid use disorder

oxycodone

- morphine opioid analgesic that is more potent than codeine and is used in pain

hydrocodone

- morphine opioid analgesic that is used in pain and cough

tramadol

- synthetic opioid analgesic

fentanyl

- synthetic opioid analgesic that is more potent than morphine and is used in severe pain and sedation

- full agonist at MOR and ~50-100 times more potent than morphine after systemic delivery (extremely potent analgesic)

- accounts for the rapid increasing rates of overdose death

methadone

- synthetic opioid analgesic that is used in opioid dependence (less craving) and pain

- mu agonist that is more selective to mu than morphine

- can reduce symptoms of withdrawal and reduce craving

- one of the most common medicines used to treat opioid dependence

current strategies for safer opioids

- G protein-based and B-arrestin-biased agonists that allow for receptor internalization

- biased agonism produces more precise therapeutic effects

- identification of biased ligands at GPCRs became a standard approach in GPCRs drug discovery

Olinvyk (oliceridine)

- a G protein based mu-opioid agonist

- approved for acute pain management in certain adults for short-term IV use in hospitals and other controlled clinical settings

naloxone

- mu-opioid receptor antagonist/competitive MOR antagonist

- CNS acting

- rapid metabolism

- acts within minutes and lasts ~1 hour

- used for treating acute opioid overdose and alcoholism opioid abuse

- can NOT reverse fentanyl overdose - need repeated doses

naltrexone

- mu-opioid receptor antagonist/competitive MOR antagonist

- CNS acting

- first-pass liver metabolite

- acts in ~30 minutes and lasts a day

- can NOT treat acute opioid overdose

- used for treating alcoholism and drug craving

MOR ligand agonist

- morphine

- used for analgesia

- high risk of adverse effects including respiratory depression, constipation, and addiction

MOR ligand partial agonist

- buprenorphine

- used for analgesia and the treatment of addiction

- lower risk of adverse effects

MOR ligands antagonist

- naloxone

- used for counteracting drug overdose

- no opioid analgesic effect or adverse effects

neurons (nerve cells)

- electrically excitable cells that express a variety of ion channels and ion transporters that allow them to conduct impulses or action potentials that ultimately trigger release of neurotransmitters during chemical neurotransmission

- consist of 3 parts = dendrite, cell body (soma), axon

dendrites

- part of neuron that recieves input from other cells

- recieves electrical stimulation

soma

- cell body of neuron

- contains nucleus

axon

- part of neuron through which action potential is generated and travels the length of to cause the release of neurotransmitters

- responsible for transmitting electrical impulses away from nerve cell body

axon terminal

- part of neuron which contains vesicles that store neurotransmitters for release at the synapse

communication between neurons

- an electrical signal travels down the axon, chemical neurotransmitter molecules are released, neurotransmitter molecules bind to receptor sites

- signal is picked up by the 2nd neuron and is either passed along or halted

- signal is also picked up by the 1st neuron causing reuptake of some of the released neurotransmitter

criteria of NTs

- chemical must be synthesized in the neuron

- when neuron is active the chemical must be released and produce a response in some target

- same response must be obtained when the chemical is experimentally placed on the target

- a mechanism must exist for removing the chemical from its site of activation after its work is done

types of NTs

- classified by the nature of material = amino acids, peptides, monoamines

- classified by function/effect = excitatory (glutamate), inhibitory (GABA), other psychological function (dopamine, serotonin, norepinephrine)

excitatory NTs

- glutamate (>90% of the synapses)

inhibitory NTs

- GABA (>90% of the synapses that don't use glutamate)

serotonin

- NT found in the enteric nervous system (ENS) and central nervous system (CNS)

- biosynthesis from tryptophan through a 2-step pathway

- 90% is synthesized and stored in GI tract and blood platelets

- also synthesized in brain where it performs its primary functions

serotonin biosynthesis

- tryptophan converted to 5-hydroxytryptophan by tryptophan hydroxylase

- 5-hydroxytryptophan converted to 5-HT/serotonin by decarboxylase

serotonin metabolism

- mainly is metabolized in the liver to 5-HIAA by oxidative deamination by MAO and the aldehyde is then converted to 5-HIAA by aldehyde dehydrogenase or reduced to an alcohol

- melatonin is a metabolite by N-acetylation and O-methylation that serves a role in regulating circadian rhythms and shows promise in the treatment of sleep disturbances

- metabolites are excreted from urine

serotonin primary functions performed in brain

- influences a multitude of functions including sleep, cognition, sensory perception, motor activity, temperature regulation, nociception, mood, appetite, sexual behavior, and hormone secretion

- 5-HT neurons are principally in raphe nuclei of the brainstem and project throughout the brain and spinal cord

- control sleep-wake cycle, aggression and impulsivity, appetite and obesity

5-HT and 5-HT receptors in brain

- biosynthesized from tryptophan and packed in vesicle in presynaptic neuron

- released into synapse and activates cell-specific postsynaptic receptors leading to signal transduction

- taken up by 5-HT transporter (SERT) to terminate 5-HT action

- reuptake of 5-HT allows it to be either repacked in vesicle or metabolized by monoamine oxidase

5-HT receptors and functions

- 7 general 5-HT receptor families including 14 serotonin receptors

- all serotonin receptors are GPCRs except 5-HT3 which is a ligand-gated Na+ and K+ ion channel

serotonin signaling and depression and anxiety

- in general an imbalance/deficiency of the monoamine NTs (serotonin, norepinephrine, dopamine), particularly serotonin, may lead to depression

clinical significance of affecting 5-HT signaling

- act at monoamine oxidase (in presynaptic)

- act at 5-HT transporters (on presynaptic)

- act at 5-HT receptors (on postsynaptic)

pharmacotherapy for depression

- selective serotonin reuptake inhibitors (SSRIs)

- serotonin-norepinephrine reuptake inhibitors (SNRIs)

- tricyclic antidepressants (TCAs)

- serotonin antagonists and reuptake inhibitors (SARIs)

- serotonin modulators and stimulators (SMSs)

- norepinephrine reuptake inhibtors (NRIs)

- norepinephrine-dopamine reuptake inhibitors (NDRIs)

- monoamine oxidase inhibitors (MAOIs)

SSRIs

- reuptake of 5-HT into presynaptic terminals is mediated by SERT

- neuronal uptake is the primary process by which neurotransmission via 5-HT is terminated

- block reuptake of 5-HT to enhance and prolong serotonergic neurotransmission

- effective in treating major depressive disorder (MDD) and also used as anxiolytics in the treatment of generalized anxiety, panic, social anxiety, and OCD

- first-line drug for depression due to effectiveness and a lower risk of side effects compared to older antidepressants

- FDA black box warning = antidepressants may increase the risk of suicide in patients under 25

citalopram

- SSRI

- has a chiral center, 2 isoforms, sold as racemic mixture

- S-citalopram (escitalopram) less selective for SERT than citalopram

- used in treating major depressive disorder (MDD)

- common side effects = sexual dysfunction and abnormal heart rhythm

- serious side effect = increased risk of suicide in patients under 25

- discontinuation symptoms = electric shock sensations (brain shivers), dizziness, acute depression

- overdose may result in sedation, dizziness, tremors; deaths have occurred

citalopram metabolism

- metabolized in the liver mainly by CYP2C19 and 3A4/2D6

- 80% cleared by the liver and 20% cleared by the kidney

citalopram drug interactions of

- may increase risk of bleeding if using together with NSAIDs, warfarin, and other blood thinners

- lead to serotonin syndrome (high body temp, agitation, etc.) if taken with St. John's wort (inhibits 5-HT reuptake) or other SSRIs

sertraline

- SSRI

- most commonly prescribed psychiatric medicine in the US

- treatment of MDD, OCD, PTSD, panic disorder, social anxiety disorder, etc.

- common side effects = sexual dysfunction and abnormal heart rhythm

- serious side effect = increased risk of suicide in patients under 25

- discontinuation symptoms

- its toxicity in overdose is considered relatively low as with most other SSRIs

- major metabolite norsertraline is less active than sertraline

paroxetine

- SSRI

- metabolized in liver by CYP2D6, 3A4, and 1A2 via demethylation and dealkylation

- same common side effects as other SSRIs

- increased risk of suicide in patients under 25

- discontinuation symptoms

- overdose may result in nausea, vomiting, sedation, dizziness, sweating, seizures

fluvoxamine

- SSRI

- first SSRI approved for the treatment of OCD; also for the treatment of depression and anxiety disorders

- has E configuration

- same common side effects as other SSRIs

- has more GI side effects than other SSRIs

fluoxetine

- SSRI

- sold as racemic mixture

- metabolized in the liver by CYP2D6

- major metabolite is demethylated product norfluoxetine

- both fluoxetine and norfluoxetine inhibit CYP2D6

- has extremely long half-life which makes it less common to develop discontinuation syndrome following cessation of therapy compared to other SSRIs (elimination in 1-3 days)

SNRIs

- medications with a non-tricyclic structure that inhibit the reuptake of both 5-HT and NE approved for treatment of depression, anxiety disorders, pain, etc.

- FDA black box warning = antidepressants may increase the risk of suicide in patients under 25

- inhibit both SERT and NET and cause serotonergic or noradrenergic neurotransmission

- may improve overall treatment response compared to SSRIs

- repeated treatment reduces the expression of SERT or NET resulting in reduced neurotransmitter clearance and increased serotonergic or noradrenergic neurotransmission

venlafaxine

- SNRI

- sold as racemic mixture

- reserved as second-line treatment for depression due to a combination of its superior efficacy to the first-line SSRI treatments and greater frequency of side effects

- patients taking venlafaxine had significantly higher risk of completed suicide than the ones taking SSRIs

- metabolized in the liver by CYP2D6

- major metabolite is desvenlafaxine which is as potent as venlafaxine

desvenlafaxine

- SNRI

- major metabolite of venlafaxine that is more potent (higher binding affinity to both SERT and NET) and is able to be continually metabolized

duloxetine

- SNRI

- S-enantiomer inhibits serotonin reuptake to twice the degree of R-enantiomer

- metabolized in liver by CYP2D6 and 1A2

- major metabolites are inactive

tricyclic antidepressants (TCAs)

- act primarily as SNRIs by blocking SERT and NET but lack selectivity to at SERT and NET

- many also have high affinity as antagonists at 5-HT2, 5-HT6, 5-HT7, a-adrenergic, and NMDA receptors, and as agonists at the o receptors

- replaced by newer antidepressants such as SSRIs, SNRIs, and NRIs

- primarily used for the treatment of mood disorder, anxiety, panic disorder, PTSD, ADHD, Parkinson's, chronic pain, etc.

- structure composed of 7-membered ring with 2 benzene rings and a 3-C linker that leads to a basic amine attached

dibenzazepines

- TCAs that end in -ipramine

- structure contains "N" on 7-membered ring that attaches to 3-C linker

dibenzocycloheptadines

- TCAs that end in -triptyline

- structure contains double bond on 3-C linker attached to 7-membered ring

dibenzoxepines

- TCA = doxepin

- structure contains "O" on 7-membered ring adjacent to a benzene ring (not attached to 3-C linker)

imipramine

- TCA

- inhibits SERT and NET

- antagonize a1-adrenergic receptors

- primarily used to treat major depressive disorder (2nd line antidepressant)

- metabolized to desipramine, a 5-HT and NE reuptake inhibitor

amitriptyline

- TCA

- inhibits SERT and NET

- potent non-selectively block multiple ion channels

- primarily used to treat major depressive disorder (2nd line antidepressant) and used to treat neuropathic pain

- metabolized to nortriptyline, a stronger NE reuptake inhibitor

tetracyclic antidepressants

- atypical, 4-ringed antidepressants

- inhibits the central presynaptic a-2-adrenergic receptors to cause an increased release of 5-HT and NE

- mirtazapine

serotonin antagonists and reuptake inhibitors (SARIs)

- antagonize 5-HT2 (primarily 5-HT2A) to mediate its therapeutic benefits against anxiety and depression

- also weakly inhibit the reuptake of 5-HT

- effective drugs for depression and anxiety disorder and alcohol dependence

- efficacy may be more limited than that of SSRIs

trazodone

- SARI

- potent 5-HT2A antagonist and weak SERT inhibitor

- metabolized in liver by CYP3A4 to produce 4 major metabolites

- metabolite mCCP is a psychoactive drug of the phenylpiperazine class; metabolized by CYP2D6

- mCPP possesses significant affinity for 5-HT receptors and SERT, acts as an agonist at most 5-HT receptors, but may contribute to side effect profile of trazodone including blurred vision, dizziness, nausea, dry mouth, headache, somnolence, fatigue, etc.

nefazodone

- SARI

- potent 5-HT2A antagonist and weak SERT inhibitor

5-HT1 receptor agonists

- 5-HT1A receptors expressed in the presynaptic neuron (B, autoreceptor) inhibit the reuptake of 5-HT

- 5-HT1A receptors expressed in other region (C) are involved in neuromodulation

- clinical significance = antianxiety, antidepressant, anti-aggressive, anti-craving, anti-cataleptic, and neuroprotective properties

- less effective than SSRI

- commonly used as add-ons to other antidepressants such as SSRIs

azapirones

- 5-HT1 receptor agonist

- structural feature = long-chain

- metabolized in liver to the common metabolite pyrimidinylpiperazine

- buspirone

vilazodone

- partial agonist at 5-HT1A

- inhibits SERT and also inhibits NET and DAT

- major metabolite is hydroxyvilazodone

schizophrenia

- a serious mental illness that affects how a person thinks, feels, and behaves

- symptoms fall into 3 categories = psychotic, negative, and cognitive

- typically diagnosed in the late teen years to the early 30s and tends to emerge earlier in males than females

psychotic symptoms of schizophrenia

- altered perceptions, abnormal thinking, and odd behaviors

negative symptoms of schizophrenia

- loss of motivation, diminished feelings of pleasure in everyday life, difficulty showing emotions, etc.

cognitive symptoms of schizophrenia

- problems in attention, concentration, and memory

the dopamine (DA) hypothesis of schizophrenia

- in 1963 Dr. Carlsson proposed that disturbed and hyperactive dopaminergic signal transduction, particularly in the prefrontal region, results in schizophrenia symptoms

- based on the discovery and clinical effects of two dopamine receptor D2 antagonists (chlorpromazine and haloperidol)

- resulted in the development of typical/1st generation antipsychotic agents (D2 antagonists)

4 dopaminergic pathways in brain

- mesocortical pathway = prefrontal cortex, cognitive function (schizophrenia)

- mesolimbic pathway = nucleus accumbens, reward (addiction)

- nigrostriatal pathway = striatum, voluntary movement (Parkinson's)

- tuberoinfundibular pathway = pituitary, secretion of prolactin (milk)

1st generation antipsychotics

- D2 antagonists associated with extrapyramidal side effects (EPS)

- EPS = drug-induced movement disorders with symptoms including dystonia, akathisia, and parkinsonism (muscle contractions, motor restlessness, rigidity, etc.)

2nd generation antipsychotics

- stimulated by the discovery of clozapine in 1963 which binds to dopamine receptor (D2) as well as serotonin receptor (5-HT)

- potently antagonize the 5-HT2A receptor while possessing less affinity for D2 receptors than typical antipsychotic agents

- antagonists at 5-HT2A and D2 or antagonists at 5-HT2A and partial agonist at D2

- generally have antipsychotic efficacy with lower potential for EPS side effects

limitations of the DA model of psychosis

- exact molecular mechanism of psychosis has not been completely revealed

- does not explain the psychotomimetic effects of some drugs that do not activate D2 receptor such as LSD (potent 5-HT2A receptor agonist), phencyclidine, and ketamine

- NTs dopamine, serotonin, and GABA may all have effects of psychotic disorders

phencyclidine and ketamine

- NMDA glutamate receptor antagonists

- indirectly act to stimulate DA availability by decreasing the glutamate-mediated tonic inhibition of DA release

biochemical processes of DA

- biosynthesis = phenylalanine > tyrosine > L-dopa > dopamine

- DA is stored in vesicle (presynaptic) and released to synapse after triggered by an electrical stimulation

- binds to dopamine receptors to transduce signal or is taken up by DAT to stop signal then metabolized or restored in vesicle

dopamine receptors

- D1, D2, D3, D4, D5 subtypes are all GPCRs (two families)

- D1-like family coupled to Gs protein = D1 and D5

- D2-like family coupled to Gi protein = D2, D3, D4

D2 receptor

- main receptor for most antipsychotic drugs

- postsynaptic D2 = classic GPCR

- presynaptic D2 = autoreceptor that regulates the levels of DA in the synaptic cleft which activates presynaptic D2 and inhibits DA release

1st generation (typical) antipsychotics

- direct interaction with postsynaptic D2 type receptor

- D2 antagonists (most potent/greatest affinity at D2)

- many drugs also have appreciable affinity at other receptors (low selectivity D2 ligands)

- associated with higher risk of EPS (a movement disorder including continuous muscle contractions, motor restlessness, rigidity, etc.)

- representative type of drugs = phenothiazine (major) and thioxanthene

phenothiazine antipsychotics SAR

- containing phenothiazine core

- crystal structure partially overlaps with dopamine

- on the A ring an electronegative group (Cl, CF3, SCH3) is responsible for the asymmetry to the molecules

- electronegative group attracts the amine side chain toward the ring containing the electronegative atom

- electronegative group is crucial to activity (phenothiazines lacking the electronegative group at this position are inactive)

- side chain amine requires three carbons separating two nitrogen atoms (two-carbon side-chain separation does not have activity)

prochlorperazine

- 1st generation (typical) antipsychotic/phenothiazine

- used in the treatment of schizophrenia, psychosis, nausea, and migraines

- common side effects = sedation, EPS, and acute withdrawal syndrome if discontinued abruptly

thioxanthene antipsychotics SAR

- structurally related to phenothiazine

- containing an olefinic double bond between tricyclic ring and the side-chain

- exist in cis (Z) or trans (E) configurations

- cis isomer is 7-fold more active than trans isomer

butyrophenone antipsychotics SAR

- phenone = aromatic ketone containing a phenyl group directly attached to a carbonyl group

- tertiary amino group attached at 4th carbon of the butyrophenone skeleton

- haloperidol (Haldol)

haloperidol (Haldol)

- 1st generation (typical) antipsychotic/butyrophenone

- discovered in 1958

- first antipsychotic medicine acting at D2 receptor

2nd generation (atypical) antipsychotics

- interact with D2-type receptor and 5-HT receptor and act as D2 antagonist/partial agonist and 5-HT2A antagonist

- many drugs also have appreciable affinity at other receptors (low selectivity D2 ligands)

- lower risk of EPS than 1st generation due to high affinity for 5-HT2A and reduced affinity for D2

- representative structures = dibenzodiazepine and long-chain arylpiperazine

clozapine

- first atypical (2nd generation) antipsychotic (prototype)

- has minimum EPS and does not produce uncontrollable face and body movements (tardive dyskinesia) with long-term use

- effective in patients who do not respond to typical first-generation antipsychotics

- metabolized mainly by CYP1A2 and also by CYP3A4

- cigarette smoking induces activity of CYP1A; patients who smoke while taking clozapine have significantly lower serum levels of clozapine

- consume caffeine-containing beverages while taking clozapine increases EPS as caffeine is metabolized primarily by CYP1A

- significantly most effective!

olanzapine

- 2nd generation atypical antipsychotic

- metabolized by CYP1A2 and UDPGT

quetiapine

- 2nd generation atypical antipsychotic

risperidone

- WHO's list of essential medicines as the safest and most effective medicines needed in a health system

- produces more EPS than most other atypical antipsychotics

- metabolized mainly by CYP2D6

ziprasidone

- 2nd generation atypical antipsychotic

- metabolized mainly by CYP3A

lurasidone

- 2nd generation atypical antipsychotic

- metabolized mainly by CYP3A

aripiprazole

- 2nd generation atypical antipsychotic