Phar 402 Cholinergic System Functions Jaki

Front 1

identify the sites at the cholinergic synapses which can be regulated by drugs and explain how a given drug molecule may act to modify the cholinergic responses.

Back 1

7 steps/sites at the cholinergic synapse that can be regulated by drugs:biosynthesis of Ach, uptake of choline, release of Ach, postynaptic receptors, metabolism of Ach by AChE, presynaptic receptor (Autoreceptor)

Front 2

how is the biosynthesis of Ach by choline acetyltransferase (ChAT) inhibited by drugs?

Back 2

inhibited by NVP. Napthalene ring binds to the acetyl side, protonated pyridine ring binds to the choline side

Front 3

how does NVP bind and inhibit ChAT?

Back 3

* the napthalene ring binds to CoA site
* the protonated pyrdidine ring must be competing with ACh binding site to the anionic binding site (where the quat ammonium of choline binds)

Front 4

how is uptake up of choline inhibited by drugs, competively?

Back 4

hemicholinium-3 is a competitive choline uptake inhibitor. it has an open ring structure that resemblers choline and can’t cross membrane because it binds to two carrier molecules at the same time and are immobile

Front 5

how is uptake of choline inhibited by drugs, falsely?

Back 5

Triethylcholine(TEC). False NT competes with choline for uptake in presynaptic. along with entering the nerve membrane and competing with choline for biosynthesis of Ach. triethylacetylcholine acts as a false NT bc it doesn’t have Ach activity.

Front 6

how is uptake of choline inhibited by drugs, non-competively?

Back 6

L-vesamicol, a non-competitive inhibitor. works by inhibiting the process by which acetylcholine is actively transported into synaptic vesicles

Front 7

how is release of Ach inhibted by drugs, ab?

Back 7

tetracycline binds to free Ca and reduces its concentration, therefore Ca can’t induce the vesicles to fuse with the membrane

Front 8

what drugs inhibit the release of Ach ?

Back 8

* blocked by botulinum toxin, cytocholasin B, Mg2+
* inhibits the release of Ach from the neuromusclular junctions or motor neurons (cleaves SNAP-25=protein esential for successful docking and release of Ach from vesicles situated within nerve endings)

Front 9

which toxins cause extreme release of Ach?

Back 9

beta-bungarotoxin and La3+ cause exhaustion of Ach sotres in nerve terminal and prevent further release of Ach concentration

Front 10

explain how acetylcholine is biosynthesized

Back 10

Acetycholine is synthesized from adding a acetyl group onto choline...the acetyl group is donated from acetyl co-enzyme A which binds to the enzyme choline acetyl transferase which makes Ach.

Front 11

how is Ach, stored, released and inactivated?

Back 11

Ach is stored in presynaptic vesicles and released upon depolarization of the presynmaptic terminal when Ca rushes into the pre-cell. it get inactivated through reuptake of the NT or being modified by acteylcholine esterases which degrade the NT. also competition with an antagonist lessens its effect.

Front 12

what is the structure of nicotinic receptor (nAChR)?

Back 12

nicotinic receptor is a transmitter gated ion channel. it causes a change in ion concentration. heteromeric with 5 subunits. alpha subunit contains Ach binding sites and connecte by disulfide bonds

Front 13

what compounds block and stimulate nicotinic ACh receptors ?

Back 13

stimulated by nicotine and blocked by d-tubocurarine, C6 and C10

Front 14

what compounds block and stimulate muscarine ACh receptors?

Back 14

stimulated by muscarine and blocked by atropine

Front 15

where are musarinic receptors located?

Back 15

all postganglionic parasympathetic nerve endings

Front 16

where are nicotinic ach receptors located?

Back 16

autonomic ganglia and at Neuromusclular junctions

Front 17

what are some of the CV effects of nicotine?

Back 17

modulates respiration, HR, BP

Front 18

what are some of the CNS effects of nicotine in potentiating NT release ?

Back 18

suppression of appetite, antinociception, increase in spontaneous activity, memory enhancement, release dopamine

Front 19

explain nicotine tolerance

Back 19

after opening of the canal and binding of Ach, the receptor is desensitived before regenerated.
Chronic exposure leads to overstimulation of the nicotinic receptor and then the receptor is long-term inactivated and its regeneration is prevented by nicotine.
chronic activation of these receptors is balanced by a down regulation in the number of active receptors.
this reduction reduces effect of nicotine and leads to tolerance

Front 20

what is the model toxin and how does it work in looking at the nicotinic cholinergic receptor?

Back 20

alpha-bungarotoxin from snake venom binds to the alpha and beta subunits of the nAchR and likely blocks both the ionic channel and the Ach binding site. (binding the disfulide bridge irreversibly)

Front 21

what is the biochemical structural properties of the muscariinic receptor?

Back 21

GPCR (7TM). 3 subtypes.

Front 22

what are the 3 main subtypes of the muscarinic receptor?

Back 22

M1 - neuronal
M2 - Cardiac
M3 - glandular/smooth muscle type

Front 23

what is the rational behind antagonist binding to the muscarinic receptor more than agonist?

Back 23

resting/inactive receptor conformation with affinity for antagonist binding but low affinity for agonist binidng. vice versa with active conformation

Front 24

relate the structural features of a compound to its cholinergic receptor selectivity. what is the prefered receptor bound conformation of Ach?

Back 24

* with Ach, the most preferred position in the receptor is in the anticlinal (+ac) position of the molecule where it is most flexible. the charged quaternary ammonium group of Ach is important to for binding to the muscarinic receptors. a minimum of 2 methyl groups on the charged functional group is needed for agonist activity.
* +90 to +150 degrees

Front 25

what are the major requirements for ammonium group of Ach to be an agonist?

Back 25

* a positively charged functional group is needed
* a minimum of 2 methyl groups on the charged functional group is essential for agonist activity

Front 26

what are the major requirements for the ETHYLENE BRIDGE of Ach to be an agonist

Back 26

most important is the steriochemistry at the beta carbon. the S configuration is more active than the R

in S-config the methyl substitution causes less steric hindrance to the muscarinic receptor

Front 27

what are SAR modifications that can be done at the ETHYLENE BRIDGE of Ach?

Back 27

* beta methyl substitution produces selective muscarinic agonist.
* alpha methyl substitution makes a selective nicotinic agonist

Front 28

what is the effect of a CARBAMOYL replacement on the acetyl group of Ach?

Back 28

* get carbachol an orally active nicotinic and muscarinic agonist.

Front 29

what is the effect of adding a BENZYL group to replace acetyl group of Ach? and adding an -OH?

Back 29

* get a partial agonist/antagonist with just the benzyl group
* get a muscarininc antagonst with the OH

Front 30

how does Delecit work for tx of attention and memory disorders in the olde people?

Back 30

* delecity increase the level of choline needed for biosynthesis of Ach in the brain.
* it can be acylated by lipases in intestine to make phosphotidylcholine which can penetrate BBB.
* can easily be degraded by phosphate enzymes in periphery and choline can be taken into brain.

Front 31

explain where an agonist must correctly place residues in the clothia model for muscarinic receptor-cholinergic drug interaction

Back 31

* a methyl in C7
* a positively charged ammonium group with 2 methyls in C1 and C3
* A hydroxy or oxygen function projected upward in O2 position.

Front 32

what side does the nicotinic binding hit?

Back 32

* carbonyl O2 side
* Carbonyl side is preserved, methyl side blocked

Front 33

what side does muscarinic binding hit?

Back 33

* binds from the methyl side (c7)
* methyl side preserved, carbonyl side blocked
* muscarine’s ring blocks binding on carbonyl side so binds methyl

Front 34

Back 34

Acetycholine (NT)

Front 35

Back 35

muscarine
muscarinic agonist

Front 36

Back 36

nicotine
nicotinic agoninist

Front 37

Back 37

atropine muscarinic antagonist

Front 38

what brings choline uptake into cell?

Back 38

Na/dependent carrier A

Front 39

what drugs inhibit Ca release?

Back 39

succinynol choline (nicotinic antagnoist depolariers), tetracycline

Front 40

how does alpha bungarotoxin bind and inhibit?

Back 40

binds to the alpha and beta subunit of the disulfide and keeps ion channel closed

Front 41

what kind of function?

Back 41

orally active muscarinic agonist

Front 42

what are the binding sites for nicotinic and muscarinic binding?

Back 42

Front 43

Back 43

carbamate ester-type reversible AChE inhibitor. physostigmine

Front 44

wat

Back 44

carbamate ester-type reversible AChE inhibitors. neostigmine