Lecture 6: how do drugs work Flashcards
Four primary drug tagets?
- ion channels
- enzymes
- carrier molecules
- receptors
the only exception being DNA for which some anti-tumour drugs and antimicrobial drugs bind to
4 steps of neurotransmission
- synthesis
- release
- receptors
- inactivation
key sites of action of drugs in neurotransmitter:
synthesis
release
reception
- choline trnsporter (for ACh synthesis)
Choline acetyl transferase (ChAT) -for choline synthesis
- Vesicular ACh transporter acks ACh into vesicles
Ca 2+ causes vessicle binding to membrane
- Ligand gated ion channels, G-protein couples receptors, tyrosine/cytokine kinase receptors, steroid/nuclear hormone receptors
4 types of channels
Ligand gated ion channels features?
- fast signal transmission
- multi-subunit complexes
- responds to specific ligands, select ions to let through
- conduct these ions through otherwise impermeable membranes
nicotinic acetylcholine receptors
the receptor pore?
- 5 subunits arranged around central channel
- each subunit has 4 transmembrane domains (20 total)
- each binding site sits between alpha subunit and adjacent subunit
- both binding sites needed to be occupied for channel opening
- onened by ACh binding
- aa in TM2 determies conductivity (usually Na+ and K+)
Ionotropic receptors as drug targets?
GABAA -Benzodiazapines and barbiturates (sedation and anxiolytic effects). Muscimol (hallucinogenic mushrooms)
Glutamate - ketamine (anaesthetic) have adverse effects
Nicotinic - nicotine, pancuronium (antagonsist) used as a muscle relaxants during anaesthetic
GPCRs?
- 7 transmembrane domains
- intracellular C terminal interacts with G protein
- Gαs = activates adenyl cyclase, ↑cAMP
- Gαi = inhibits adenyl cyclase, ↓cAMP
- Gαq = activates PLC (PIP2 —> DAG + IP3)
- Use Muscarinic receptors M1,2,3,4,5
GPCR pre-synaptic receptors?
- usually Gi linked
- activation leads to inhibition of voltage sensitive Ca2+ channels
- results in decreased neurotransmitter release
- FEEDBACK LOOP
- drugs can be targeted to block these decreasing release 10 fold
tyrosine kinase receptors
- receptor functions as an enzyme that transfers phosphate groups from ATP to tyrosine residues on intracellular target proteins (autophosphorylation)
- mediate action of growth factors, cytokines and certain hormones (eg insulin)
vascular endothelial growth factor receptors
- essential for angiogenesis during development, pregnancy, woud healing
- also in pathophysioloical conditions: cancer, rheumatoid arthritis, CVD
VEGFR2?
- ligand stimulated receptor dimerisation
- autophosphorylation of tyrosine residues in cytoplasmic domain
- associated with SH2 domain proteins
- work via big cascades (proliferation pathways)
proliferation pathways?
- receptor activation leads to PLCy activation by phosphorylation
- this hydrolyses PIP2 to DAG and IP3
- DAG activates PKC
- PKC activation leads to activation of ERK via Raf and MEK
- ERK activation leads to increased gene transcription
how do drugs bind to receptors? weak to strong
- Ven der waals forces
- hydrogen bonding
- ionic
- covalent - irreversible
Kd?
affinity constant = concentration when 50% is bound
affinity of drug
higher affinity means more binding for same conc
affinity vs biological response
is NOT LINEAR and is dependent upon many factors downstream usually
C50
potency- 50% of max response is observed determines this. Higher the conc at C50 the lower the potency
efficacy?
ability of a drug to bind to a receptor and cause a change in the receptor’s action
positive efficacy = agonist
negative efficacy = inverse agonist
no efficacy (binds but has no effect ie. it doesn’t activate or inactivate it just stops other things binding) = antagonist
different tyoes of antagonists
- reversible competitive
- irreversible
NB: sometimes irreversible can appear reversible if the % occupacy of receptor required for max effect is very low
mechanism of neurotrans inactivation?
transport back
enzymatic degradation
Serotonin (5HT) transporter
5HT is involved in sleep, apetite, memory, sexual behavior
reuptake determines extent and duration of receptor activation
SSRI’s such as fluoxetine block thismaking you happy
