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Medicinal Chemistry > Lecture 7 - Nicotinic and Muscarinic Receptors > Flashcards

Lecture 7 - Nicotinic and Muscarinic Receptors Flashcards

1
Q

What does stimulation of the adrenal medulla cause?

A

Release of adrenaline (epinephrine)

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2
Q

Nicotinic ganglionic receptors use ____ as the neurotransmiter

A

Acetylcholine

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3
Q

Muscarinic receptors use ___ as the neurotransmitter

A

Acetylcholine

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4
Q

Where is acetylcholine used as a neurotransmitter?

A
  • At all autonomic ganglia
  • At all synapses btwn somatic motor nerves and skeletal muscles
  • At all para postganglionic sites
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5
Q

What are the receptors of the somatic nervous system?

A

Nicotinic cholinergic

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6
Q

What occurs at the ACh synapse?

A
  • Action potential causes Ca2+ into presynaptic cell
  • Ca2+ is a signal for the fusion of presynaptic vesicle to presynaptic membrane
  • ACh dumps into synapse and AChE very rapidly breaks it down into choline and acetate
  • Choline is transferred into presynaptic cell and binds w/ acetyl-CoA (catalyzed by choline acetyl transferase) to make ACh and cycle starts over again
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7
Q

What happens to ACh when it is in the synapse?

A

Binds to receptors on postsynaptic cell

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8
Q

What terminates the signal that causes the release of ACh?

A

AChE

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9
Q

What effect does the symp NS have on the heart and which receptor is involved?

A
  • Beta 1 increases heart rate

- Beta 1 increases contractile force

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10
Q

What effect does the para NS have on the heart and which receptor is involved?

A
  • M2 decrease heart rate

- M2 decreases contractile force

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11
Q

What effect does the symp NS have on the blood vessels and which receptor is involved?

A
  • Alpha 1 causes constriction of arterioles

- Beta 2 causes dilation of arterioles in muscle

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12
Q

What effect does the para NS have on the blood vessels and which receptor is involved?

A

No effect

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13
Q

What effect does the symp NS have on the lungs and which receptor is involved?

A

Beta 2 causes dilation of bronchi smooth muscle

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14
Q

What effect does the para NS have on the lungs and which receptor is involved?

A
  • M3 causes constriction of bronchi smooth muscle

- M3 causes secretion of mucous

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15
Q

What effect does the symp NS have on the GI tract and bladder and which receptor is involved?

A
  • Alpha 1, alpha 2, and beta 2 cause decreased smooth muscle motility and contraction
  • Alpha 2 and beta 2 cause sphincter constriction
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16
Q

What effect does the para NS have on the GI tract and bladder and which receptor is involved?

A
  • M3 causes increased smooth muscle motility and contraction
  • M3 causes sphincter dilation
  • M3 causes acid secretion of parietal cells
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17
Q

What effect does the symp NS have on the eye and which receptor is involved?

A
  • Alpha causes pupil dilation

- Beta causes slight relaxation of ciliary muscle

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18
Q

What effect does the para NS have on the eye and which receptor is involved?

A
  • M3 causes pupil constriction

- M3 causes ciliary muscle constriction

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19
Q

All cholinergic receptors bind ____ for activity

A

ACh

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20
Q

How are the 2 types of cholinergic receptors differentiated?

A

By their affinity for 2 agonists (nicotine and muscarine)

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21
Q

What are the types of nicotinic receptors?

A
  • Nicotinic ganglionic (also nicotinic neuronal)

- Nicotinic cholinergic

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22
Q

What does depolarization at NMJ cause?

A

Action potential, which propagates muscular contraction via nearby voltage-gated Na+ channels

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23
Q

What do depolarizing neuromuscular blockers do?

A
  • Initially cause an action potential and propagate muscular contraction
  • Continued stimulus results in increased resting membrane potential
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24
Q

What can happen overtime w/ continued stimulation of nicotinic cholinergic receptors?

A

Increased resting membrane potential => nearby voltage-gated Na+ channels become refractory and no muscular contraction is propagated

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25
What is the structure of most competitive nicotinic cholinergic antagonists?
Have 2 N+ at a distance of about 11.5 A
26
What do competitive nicotinic cholinergic antagonists cause?
Non-depolarizing neuromuscular block
27
Do succinylcholine and pancuronium work via the same mechanism? Are they used for the same function?
- Work via different mechanisms | - Both used clinically to induce muscle relaxation during surgery
28
When is succinylcholine used and why?
- Used when desirable to have tight control of blockade | - Is rapidly hydrolyzed by esterases
29
When is pancuronium used and why?
For muscle relaxation during longer surgeries b/c of its longer duration of action
30
Are nicotinic ganglionic selective antagonists ever used?
No b/c they have too many side effects
31
Which G alpha is M1?
G alpha q
32
Which G alpha is M2?
G alpha i
33
Which G alpha is M3?
G alpha q
34
What is the tissue location of M1?
- CNS (cortex, hippocampus) - Ganglia - Parietal cells
35
What is the tissue location of M2?
- Atria and conducting tissue | - Presynaptic terminals
36
What is the tissue location of M3?
- Smooth muscle | - Vascular endothelium
37
What are the cellular effects of M1?
- Increased phospholipase C gamma, IP3, DAG, [Ca2+] - Decreased potassium outflow - Result - excitation
38
What are the cellular effects of M2?
- Decreased cAMP, [Ca2+] - Increased K+ outflow - Result - inhibition
39
What are the cellular effects of M3?
- Increased phospholipase C gamma, IP3, DAG, [Ca2+] - Decreased potassium outflow - Result - excitation
40
What is the function of M1?
- Excitation of CNS (memory) - Gastric acid secretion - GI motility
41
What is the function of M2?
- Decrease heart rate and force of contraction | - Presynaptic and neural inhibition
42
What is the function of M3?
Bladder smooth muscle contraction
43
How many transmembrane helices does a muscarinic GPCR have?
7
44
Which part of ACh is required for activity?
- N+ | - Ester
45
What happens if you remove methyl groups from ACh?
Decreases potency
46
Does ACh have conformational flexibility and what effect does this have?
- Yes - Makes binding to a receptor difficult b/c usually occurs in only one conformation - Some conformations favour binding to nicotinic while others favour muscarinic
47
What is the function of the ester on ACh?
- Important for activity and receptor binding | - Oxygen acts as H-bond acceptor
48
What happens if you replace methyl groups of ACh w/ ethyl groups?
Potency decreases, but not as much as removing methyl groups completely
49
What is important to note about the anionic site of the ACh binding site?
- Can accomodate 2 methy groups | - Have a negative charge
50
What happens when carbons are added to ACh?
- Adding 1 or 2 doesn't change intrinsic activity - Adding 3 decreases intrinsic activity - Adding 4 causes zero intrinsic activity
51
What is important to note about the ester end of ACh?
A chain longer than CH2CH2CH3 can't fit into receptor in any conformation
52
For muscarinic agonists, what is needed for optimal binding?
No more than 5 large (ie not H) single-bonded atoms long from N+
53
What happens as the length of the alkyl chain of a muscarinic agonist increases beyond 5 atoms?
Affinity and intrinsic activity decrease
54
What happens if the alkyl chain of a muscarinic agonist is greater than 7 atoms?
No activity or intrinsic activity
55
What do internal ion-dipole interactions with ACh do?
Increase polarization of carbonyl double bond
56
Carbonyl is a strong ______
Electrophile
57
Is acetylcholine susceptible to hydrolysis?
Yes, that is why it is rapidly metabolized by AChE
58
What makes ACh and carbachol different?
Carbachol has delocalized electrons, which decrease the electrophilic nature of the carbonyl C making it resistant to AChE hydrolysis
59
What makes ACh and methacholine different?
Methacholine has a methy group added as "steric shield" which decrease access to the carbonyl carbon by nucleophiles, which also sterically inhibits binding of AChE
60
What is methacholine used for?
As a test for asthma called the methacholine challenge test
61
What is bethanechol used for?
To increase urinary output
62
What is pilocarpine used for?
To treat glaucoma
63
Which muscarinic agonists are not used clinically and why?
- ACh and carbachol | - Not orally active
64
Which isomer is more potent of methacholine and bethanechol?
S isomer (when N+(CH3)3 is on right side, CH3 and H on C next to O will be pointing into the page)
65
Which isomer of methacholine is very potent?
1(S)2(S) trans isomer; has similar activity to ACh
66
What is important to note about the 1(S) isomer of methacholine?
Has no activity b/c of cis / fully eclipsed conformation
67
What must the angles be of ACh for optimal binding?
- t1 must be 180 | - t2 must be 75-95, but can get good potency between 70-120

Medicinal Chemistry (14 decks)

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