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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
Q

What is the structure of most competitive nicotinic cholinergic antagonists?

A

Have 2 N+ at a distance of about 11.5 A

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26
Q

What do competitive nicotinic cholinergic antagonists cause?

A

Non-depolarizing neuromuscular block

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27
Q

Do succinylcholine and pancuronium work via the same mechanism? Are they used for the same function?

A
  • Work via different mechanisms

- Both used clinically to induce muscle relaxation during surgery

28
Q

When is succinylcholine used and why?

A
  • Used when desirable to have tight control of blockade

- Is rapidly hydrolyzed by esterases

29
Q

When is pancuronium used and why?

A

For muscle relaxation during longer surgeries b/c of its longer duration of action

30
Q

Are nicotinic ganglionic selective antagonists ever used?

A

No b/c they have too many side effects

31
Q

Which G alpha is M1?

32
Q

Which G alpha is M2?

33
Q

Which G alpha is M3?

34
Q

What is the tissue location of M1?

A
  • CNS (cortex, hippocampus)
  • Ganglia
  • Parietal cells
35
Q

What is the tissue location of M2?

A
  • Atria and conducting tissue

- Presynaptic terminals

36
Q

What is the tissue location of M3?

A
  • Smooth muscle

- Vascular endothelium

37
Q

What are the cellular effects of M1?

A
  • Increased phospholipase C gamma, IP3, DAG, [Ca2+]
  • Decreased potassium outflow
  • Result - excitation
38
Q

What are the cellular effects of M2?

A
  • Decreased cAMP, [Ca2+]
  • Increased K+ outflow
  • Result - inhibition
39
Q

What are the cellular effects of M3?

A
  • Increased phospholipase C gamma, IP3, DAG, [Ca2+]
  • Decreased potassium outflow
  • Result - excitation
40
Q

What is the function of M1?

A
  • Excitation of CNS (memory)
  • Gastric acid secretion
  • GI motility
41
Q

What is the function of M2?

A
  • Decrease heart rate and force of contraction

- Presynaptic and neural inhibition

42
Q

What is the function of M3?

A

Bladder smooth muscle contraction

43
Q

How many transmembrane helices does a muscarinic GPCR have?

44
Q

Which part of ACh is required for activity?

A
  • N+

- Ester

45
Q

What happens if you remove methyl groups from ACh?

A

Decreases potency

46
Q

Does ACh have conformational flexibility and what effect does this have?

A
  • 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
Q

What is the function of the ester on ACh?

A
  • Important for activity and receptor binding

- Oxygen acts as H-bond acceptor

48
Q

What happens if you replace methyl groups of ACh w/ ethyl groups?

A

Potency decreases, but not as much as removing methyl groups completely

49
Q

What is important to note about the anionic site of the ACh binding site?

A
  • Can accomodate 2 methy groups

- Have a negative charge

50
Q

What happens when carbons are added to ACh?

A
  • Adding 1 or 2 doesn’t change intrinsic activity
  • Adding 3 decreases intrinsic activity
  • Adding 4 causes zero intrinsic activity
51
Q

What is important to note about the ester end of ACh?

A

A chain longer than CH2CH2CH3 can’t fit into receptor in any conformation

52
Q

For muscarinic agonists, what is needed for optimal binding?

A

No more than 5 large (ie not H) single-bonded atoms long from N+

53
Q

What happens as the length of the alkyl chain of a muscarinic agonist increases beyond 5 atoms?

A

Affinity and intrinsic activity decrease

54
Q

What happens if the alkyl chain of a muscarinic agonist is greater than 7 atoms?

A

No activity or intrinsic activity

55
Q

What do internal ion-dipole interactions with ACh do?

A

Increase polarization of carbonyl double bond

56
Q

Carbonyl is a strong ______

A

Electrophile

57
Q

Is acetylcholine susceptible to hydrolysis?

A

Yes, that is why it is rapidly metabolized by AChE

58
Q

What makes ACh and carbachol different?

A

Carbachol has delocalized electrons, which decrease the electrophilic nature of the carbonyl C making it resistant to AChE hydrolysis

59
Q

What makes ACh and methacholine different?

A

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
Q

What is methacholine used for?

A

As a test for asthma called the methacholine challenge test

61
Q

What is bethanechol used for?

A

To increase urinary output

62
Q

What is pilocarpine used for?

A

To treat glaucoma

63
Q

Which muscarinic agonists are not used clinically and why?

A
  • ACh and carbachol

- Not orally active

64
Q

Which isomer is more potent of methacholine and bethanechol?

A

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
Q

Which isomer of methacholine is very potent?

A

1(S)2(S) trans isomer; has similar activity to ACh

66
Q

What is important to note about the 1(S) isomer of methacholine?

A

Has no activity b/c of cis / fully eclipsed conformation

67
Q

What must the angles be of ACh for optimal binding?

A
  • 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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