pharmacodynamics Flashcards
major drug targets
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
nucleic acids as drug targets
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
4 types of classical receptor
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
ligand gates ion channel
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
receptor activations
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
G protein coupled receptors
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!!
GPCR subfamilies
1) rhodopsin family
2) secretin/glucagon family
3) metabotropic glutamate receptor / Ca sensor
rhodopsin family
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
secretin/glucagon family
1) receptors for peptide hormones
-ex calcitonin
2) intermediate EC tail with ligand binding domain
metabotropic glutamate receptor/Ca sensor
1) small group including GABA(B) receptors
g protein activation
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
examples of g-protein alpha subunit isoforms
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
g protein modulation of effector molecules
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
desensitization
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
TKRs
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
kinase linked and related receptors
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)
kinase linked receptor transduction mechanisms
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
SH2 domains activated by RTK linked receptors
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
nuclear receptors
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
nuclear receptor domains
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
class I
1) cytoplasm
2) homodimers upon binding before translocating
3) for steroid hormones and estrogen, progesterone, and adrogen
class II
1) nucleus
2) heterodimers
3) fatty acid and cholesterol and xenobiotics
hybrid class
1) certain members of class II
2) RXR heterodimers
3) thyroid hormone and vitamin D
mechanisms of class I nuclear receptor
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
mechanisms of class II nuclear receptor
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
summary
1) know structure of ligands
2) time scale of each class
