Topic 8: Drug Discovery Flashcards
Why do ion channels make attractive drug targets?
many types, some are tissue selective allows for manipulation of electrochemical gradients
what drug binds to the SUR subunits of the K-ATP channels and causes closing?
Sulfonylureas and meglitinides
what is an inward rectifer
allows for the infux of ions more than its efflux
why are poly aminies more attracted to the pore when the membrane depolarises?
positivly charged so more attceted to pore ass depolarisation of the memebrane
What does ATP concentration and ADP concentration do to the open probability of Kir6
high atp closes low atp opens
ADP binding casues channel openig
What does ATP concentration and ADP concentration do to the open probability of Kir6
high atp closes low atp opens
ADP binding casues channel openig
what happens to membrane potenitail when k-ATP channels open
hyperpolarasation
what is the mechanism of stimulus secretion coupling in B cells
low glucose leads to less ATP and more ADP
ADP binds to K-ATP channels- opens
deplariation causes the cloisng og CA2+ channels
less ca2+ less secreation.
how does high glucose lead to insulin secretion
high glucose extrecellular
diffuseses - more metablism more ATP less
ADP
closingof K - ATP channels
depolation of the cell
opening of Ca2+ l type channels
simulation of secreation if insulin (vescicle binding)
What happens to insulin secretion when k ATP channels are inhibited?
no hyperpolariastion so more ca2+ opening and entry and hence moere insulin secreation.
what is permenat neonatal diabeties casuesed by ?
Kir6.2 Activating mutations
two forms mild and severe
mild is caused by a mutation to the ATP binding site - favours the open state
severe is caused by a gating mutation, increased open probbality - hyperpolarisation in many tissues.
what form of permanant neonatal diabeties will respond to sulfonylourea therapy?
mild
what causes congenital hyperinsulinism? what is it treated by?
mutaion in the SUR1 binding domain, causes the cahnnelto remain closed even in high ADP concentraion trated by channel openers such as diazoxide.
what are two 5-HT antagonists?
Alosetron and ondansetron
what part of the brain controls the vomit reflex?
the vomiting centre
what ligand is the nicotinic receptor superfamily sensitive to?
5-HT - cation selective excitatory receptors
what is the 5-HT 3 receptor coupled to?
Nothing it is an ion channel (ligand gated) the other 5-HT receptors are GPCRs
what is a Cys-loop receptor?
has a signature extracellular loop of 13 amino acids flanked by cysteines, which form covalent bonds
this loop forms a closed loop between the ligand binding domains and the channel domains.
what are the two ways the vomiting reflex can be activated?
chemoreceptor trigger zone and the GI tract
Where are the highest levels of 5-HT 3 receptors found?
in the vomiting centre and chemoreceptor trigger zone
why can the chemoreceptor zone detect chemicals in the blood?
it is not within the BBB
what can the chemoreceptor trigger zone be stimulated by?
toxins in the blood
higher brain centres
how does the chemorecepror trigger zone set off the vomiting reflex?
release of 5-HT, stimulates pathways to VC
vomiting
how does the GI tract stimulate vomiting?
enetrochromaffin cells are stimulated by luminal stimuli
release of 5-HT which stimulates peripheral 5-HT 3 receptors on vagal afferents, AP to brain stem
relase of 5-HT in brain stem - stimulation of VC
What subunit is required to form functional 5-ht 3 channels
5-HT 3A
why is no current observed through 5-HT 3B-E channels?
they do not form funtional channels
What is Memantine used for?
Alzheimers - prevents neurotoxicity form excessive stimulation of glutamate receptors - slows progression
What can protein kinases do?
alter enzymic activity
alter interaction with other cellular components
alter localisation
alter stability
alter interactor specificity
what do protein phospatases do?
dephosphorylate preoteins
what is MAPK signalling
Mitogen-activated protein kinase signalling
uses a cascade of multiple kinases
how does stimulation of EGFR lead to stimulation of ERK
check in text book
agonist binding
dimerastion
activation of Grb2 and sos
Sos is a GEF for Ras
GTP for GDP exchange
phosraption of Raf
then MEK
then ERK
What do many of the current PK inhibitors bind to ?
the ATP binding site this has significant problems as high ATP in the cell - problem for competitive inhibition
most PK have similar ATP binding site this makes specificity a problem
how is pharma trying to manipulate MAPK signalling?
by interfering with lipidation- Farnesyl / geranyl traferase inhibitors- clinical efficacy but can effect other proteins
what is a novel pharmaceutical approach for pain reduction
u opioid receptor antagonism but biased to hetromer bias
may reduce tolerance build up and enhance anti noicoceptor
why might B-blockers work in CHF
reduce sympatic activation and cardiac output but aslo recued myocardial O2 demand and stress (reduced perifiral vasoconstriction
what happens to the relationship between b1 and b2 receptors in the heart as we age or in CHF
normally B1 to B2 is 4:1 but this changes to 1:1
What does the inverse agonism theory of why B blockers treat heart failure?
increase sympatetic drive leads to downregulation of B receptors
B-blockers increase receptor counts by acting as inverse agonits
What is the ligand basised theory of CHF treatment with B blockers
bindig diffrent B arrestins
diffrent signalling cascades
