pharmacodynamics

Question 1

major drug targets

Answer 1

1) classical receptors
- drug shares endogenous ligand binding site
2) ion channels
- channel blockade
- activation of channel
3) enzymes
- blockade of catalytic site
- competition for it
- drug activation by catalysis
4) transporters
- blockade of transport site
- competition for transport site

Question 2

nucleic acids as drug targets

Answer 2

1) drugs targeting DNA and RNA metabolites
- inhibit DNA and RNA regulatory proteins
- direct interaction with nucleic acids
2) intercalating agents
3) alkylating agents
- cross link
4) strand breaking
- bleomycin
5) RNA specific
- antisense
-siRNA

Question 3

4 types of classical receptor

Answer 3

1) ligand gated
- 4 or 5 membrane spanning domains
2) G protein linked
- 7 transmembrane domain
- cytoplasmic tails
3) kinase linked receptors
- 1 transmembrane domain
- cytoplasmic tails (phosphokinase domain)
4) nuclear receptors
- none

Question 4

ligand gates ion channel

Answer 4

1) pentameric complex of different subunits
2) 2 ACh binding regions near alphas subunits
3) binding of the agonist ligand or drug will straighten the pore, allowing ions to pass through
4) cation selective pore
5) notable for psychoactive drugs
6) tend not to be selective for anions

Question 5

receptor activations

Answer 5

1) neurotransmitters such as Ach or glutamate
2) very fast response time
- controls synaptic events
- direct activation aids rapidity and conversely
- direct, no mediator activation
3) conductance does not vary between endogenous or agonist drugs
4) period of opening various with agonist or drug
5) desensitization may occur when channel closes but ligand remains bound

Question 6

G protein coupled receptors

Answer 6

1) acetylcholine, (serotonin) 5HT, opioids, dopamine
2) generally consist of a single polypeptide of 11 hundred residues, 7 transmembrane alpha helices
3) N-terminal and C-terminal
4) 3 sub families
5) rapid effects!!

Question 7

GPCR subfamilies

Answer 7

1) rhodopsin family
2) secretin/glucagon family
3) metabotropic glutamate receptor / Ca sensor

Question 8

rhodopsin family

Answer 8

1) largest group
- mainly amine NTs, neuropeptides, purines, protanoids, and cannabinoids
2) short EC tail (N-terminal)
3) ligands bind to helices or extracellular hoops

Question 9

secretin/glucagon family

Answer 9

1) receptors for peptide hormones
-ex calcitonin
2) intermediate EC tail with ligand binding domain

Question 10

metabotropic glutamate receptor/Ca sensor

Answer 10

1) small group including GABA(B) receptors

Question 11

g protein activation

Answer 11

1) accessory molecules that are messengers to the 7 transmembrane unites
2) freely diffuse around the membrane and associate with target receptors
3) ligand activated receptors
- high affinity binding sites for g protein trimer complex
4) GDP occupied the alpha site, replaced by GTP on activation
- release of GTP bound alpha subunit from the receptor and beta-gamma
- finds a target effector protein
5) effector protein can be ion channel or adenylyl cyclase
- alpha subunit with self-hydrolyze to inactivate
6) beta-gamma subunit has some targets, but it is less
- deactivated alpha subunit rejoins the beta

Question 12

examples of g-protein alpha subunit isoforms

Answer 12

1) over 20 alpha subunit isoforms
2) some specificity
4) 4 families
- g alpha s
- g alpha i
- g alpha q
- g alpha 12
5) different antagonists and agonists

Question 13

g protein modulation of effector molecules

Answer 13

1) activate or inhibit effector molecule
- 2 classes of GPCR can have diff effects on it
2) depends on the stimulatory or inhibitory agonists involved

Question 14

desensitization

Answer 14

1) feature of GPC receptors
- receptor phosphorylation
- endocytosis of receptor
2) C-terminal cytoplasmic tail, serine/threonine rich and prone to kinase activity
- PKA, PKC
- specific membrane bound GPC receptor kinases GRKs
- so drug dosage may need to increase over time

Question 15

TKRs

Answer 15

1) large ligan binding domain with single membrane spanning helix
2) many structural variations of this
3) ligands are GFs, cytokines, growth hormones, lipopolysaccharides
4) inflammation, cell tissue repair, immune response, cell cycle
5) phosphorylation causes interactions with intracellular molecules with SH2 domains
6) signaling proteins are usually enzymes
- kinase cascades

Question 16

kinase linked and related receptors

Answer 16

1) RTKs
- receptors for growth factors (ex. EGF, NG)
- toll like receptors mediate response to bacterial infections (ex. caries)
2) serine threonine kinase
- TGF receptor
3) cytokine receptors
- no integral kinase moieties
- associated with cytosolic tyrosine kinases (JAK)

Question 17

kinase linked receptor transduction mechanisms

Answer 17

1) dimerization occurs on receptor binding
2) phosphorylation on intracellular domain and proteins bound to it
3) SH2 domain is serc homology domain which is what recognizes the RTKs
—
1) activation of receptor causes conformational change in intracellular portion
2) binding of intracellular kinase JAK
- phosphorylation of JAK activates other proteins like STAT

• results in transcription of specific genes

Question 18

SH2 domains activated by RTK linked receptors

Answer 18

1) many distinct pathways
2) larger family of signaling molecules
3) take time over periods of minutes to hours
- intermediate speeds to GPC receptors or ligand gated ion channels

Question 19

nuclear receptors

Answer 19

1) all are monomeric with DNA recognition and binding domain
- flexible region connector
2) ligands include vitamins and hormones
3) orphan receptors do not have defined ligand
- ex RXR receptor
4) directly interact with DNA and modulate gene transcription
- with ligand binding
5 )slowest response rate
- hours to days

Question 20

nuclear receptor domains

Answer 20

1) c-terminal domain coordinates binding receptor to the DNA
2) N terminal domain coordinates receptor to co-repressor or activator
- highly heterogeneous
- defines specificity of binding

Question 21

class I

Answer 21

1) cytoplasm
2) homodimers upon binding before translocating
3) for steroid hormones and estrogen, progesterone, and adrogen

Question 22

class II

Answer 22

1) nucleus
2) heterodimers
3) fatty acid and cholesterol and xenobiotics

Question 23

hybrid class

Answer 23

1) certain members of class II
2) RXR heterodimers
3) thyroid hormone and vitamin D

Question 24

mechanisms of class I nuclear receptor

Answer 24

1) inactive receptor associate with HSP complex
2) ligand binding initiates dissociation and translocation to nucleus
3) and binding of hormone response elements
4) the corepressors and activators then suppress or promote transcription

Question 25

mechanisms of class II nuclear receptor

Answer 25

1) not translocating because already in nucleus
2) ligand induced heterodimerization od RXR
3) corepressor and activators work the same way
- except ligand usually triggers dissociation of a bound corepressor, and allows the activator to bind

Question 26

summary

Answer 26

1) know structure of ligands
2) time scale of each class