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38 Cards in this Set
- Front
- Back
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where does Ach bind in Nicotinic receptors (what subunits) (2)
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Ach binds alpha-gamma and alpha-delta interface (mostly alpha units)
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structure of each subunit of N receptors
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4 transmembrane spanning segments
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nicotinic receptor subtypes- some susceptible to what?
these are found where? |
some subtype of nicotinic receptor are susceptible to bungarotoxins
these are tpyically the ones in the CNS |
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2 bungarotoxin sensitive subtypes of N receptors
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(a4)2(b4)3
(a7)5 |
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hemicholiniums
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chemicals that block choline transporter
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Ach biosynthesis (4)
note starting compound and enzymes involved |
choline enters cell through choline transporter
combines with acetyl CoA to make ACh enzyme: ChAT (choline acetyl transferase) packaged into vesicles |
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vesicamol
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inhibits packaging (VAT transporter) of Ach into vesicles
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2 routes of making Ach
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1) from choline
2) from serine precursor via de novo synthesis inside neuron cell |
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synthesis of Ach from serine process (4)
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1) serine- carboxylic acid cleaved off by decarboxylase
2) now we need to add a methyl group (SAM + choline NMT) 3x 3) choline 4) ChAT + Acetyl CoA + choline = Ach |
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how do we get the 3 methyl groups onto serine derivative to make choline? (2)
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N-methyltransferase
SAM (donor) |
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Ach stored in vesicles along with...(3)
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stored in presynaptic vesicles along with:
ATP, Ca++, Mg++ |
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only Ach located where is available for use?
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only Ach in vesicles is avail. as NT
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4 steps for Ach release
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initiated by action potential
opens Ca++ voltage gated channels increase Ca++ intracellularly this causes vesicular fusion of Ach-->release |
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each vesicle contains how much Ach?
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each vesicle contains 1 quanta of Ach
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1 quanta = how much Ach?
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1 quanta equals 12-60k Ach molecules
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how many quantas released per AP?
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several hundred quanta released per AP
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how is free Ach metabolized?
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1) free Ach not bound to receptor is hydrolyzed by AchE
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in avg synapse, the quantity of AchE is able to hydrolyze at what rate?
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in the avg synapse, enough AchE present to hydrolyze 3x10^8 molecules per ms
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chirality of Ach
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Ach is achiral
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dominant config of Ach
thermodynamically preferred stage vs. biologically preferred (most potent, best binding, etc) |
NMR shows synclinal? (gauch) to be the dominant config
thermodynamically preferred stage may or may not be biologically preferred |
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4 conformations of Ach moleclue
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antiperiplanar (farthest apart)
synperiplanar (close) synclinal (gauche) anticlinal (not quite as far apart- but farther than gauche) |
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how scientists found what config (antiperiplanar...etc) Ach is in that binds the best (2)
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made rigid Ach analogs
put cyclopropyl groups on molecule |
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how scientists made rigid Ach analogs
describe the structures that were made |
cyclopropane ring which allows no rotation
made cis (amine on same side as acetyl) and trans |
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biologically preferred config of Ach
which config had almost no activity? |
anticlinal (trans) found to be biologically preferred
cis had almost no activity |
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rigid Ach analog- rings
cis and trans- config? |
cis- synperiplanar
trans- anticlinal |
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4 reasons why Ach is a poor therapeutic agent
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poor specificity- binds M and N
easily hydrolyzed ester (esterase) trimethylamine meaning it is (+) so can't cross BBB poor BA (same reason) |
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3 "groups" on Ach
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ethylene (bridge)
acycloxy (COO-) quaternary ammonium group |
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3 SAR modifiable components to Ach
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1) modification of quaternary ammonium group
2 modification of ethylene bridge (the C-C that connects substituents) 3) mod of acycloxy group (the COO-) |
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how to make Ach derivative into an antagonist
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replacing all 3 methyl gruops with ethyl (or anything larger)- will lose agonist activity (becomes antagonist)
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SAR of Ach amine group- things you can modify and what will happen (3)
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arsenic, phosphorous, sulfer groups: gives less activity than Ach
-needs to be (+) replacing all 3 methyl gruops with ethyl (or anything larger)- will lose agonist activity (becomes antagonist) -adding 1 or 2 ethyls loses activity progressively (related to how many ethyls you add) replace methyl with H (making group smaller)- and change to tert, sec, primary amine you lose MUSCARINIC activity |
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Ach SAR- ethylene bridge modifications- what you can do (4)
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As chain length was increased, activity was reduced
-due to Ing's rule of 5 anything larger than Me substitution loses activity -methyl on beta carbon (C closer to acetyl) = gives muscarinic activity -methyl on alpha carbon (by N)- gives nicotinic activity |
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increasing ethylene chain length of Ach results in...
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loss of activity
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ethyl + substitution to ethylene change
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loses activity
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methyl on alpha vs beta carbon of ethylene- what happens
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alpha = nicotinic (this is C by the N)
beta = muscarinic acitivty |
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acyloxy group stability
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hydrolyzed very quickly
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main modifications to acyloxy group (3)- resulting changes in: potency, metabolism and implications for the drug
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changing to carbachol (replacing terminal C with N)- potent at both nic/musc receptors
can be administered orally as it is metabolized less make into ketone- ketones with better N receptor potency are the ones that have the carbonyl delta to quaternary nitrogen (keeps positional equivalent of the ester version) make ether- has good M activity |
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draw and label Ach and its groups
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---
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Classic SAR for M agonists- 5 main points (summary)
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have to have nitrogen with + charge, or capable of carrying + charge (preference for quaternary ammonium)
any substituents should not be larger than methyl groups (bigger = antagonist) molecule needs oxygen that can participate in H bonding such as the ester or ester like oxygen need ethylene bridge, no larger or smaller beta methyl group for M, alpha methyl for N |
