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CHEM141 > Receptors as Agonists And Antagonists - Done > Flashcards

Receptors as Agonists And Antagonists - Done Flashcards

1
Q

Define what an agonist is

A

Mimics the natural messenger and activates receptors - causing a response.

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2
Q

Define what an antagonist is

A

Drugs that bind to receptors and block but do not activate them, preventing the natural messenger from binding.

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3
Q

What must an agonist design follow?

A

Drug must have correct binding groups

Binding groups must be correctly positioned

Drug be of correct size for binding site

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4
Q

Why is chirality an important consideration in drug discovery?

A

The chiral compounds interact differently with enzymes and receptors - think thalidomide disaster

Where possible chirality is avoided

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5
Q

Define pharmacophore

A

The atoms and functional groups required for a specific pharmacological activity and their relative positions in space.

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6
Q

When chirality is necessary how do chemists get around this? What’s the issue with the other compound?

A

Asymmetric synthesis is used to only make the active compound

Inactive component - toxicity

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7
Q

What is cortisol and where does it act?

A

Anti-inflammatory — agonist - glucocorticoid receptor

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8
Q

What is cortivazol and its difference to cortisol? What does the crystal structure show?

A

Cortivazol has no ketone binding group and has 2 extra rings — agonist

Crystal structure shows different induced fit as new channel opens up, accommodating the extra rings

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9
Q

What do more binding sites mean?

A

Greater potency - additional binding sites

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10
Q

What is pharmacodynamics the study of?

A

The study of how molecules interact with targets binding site to produce a pharmacological effect

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11
Q

What is pharmacokinetics the study of?

A

The study of drug absorption, drug distribution, drug metabolism and drug excretion.

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12
Q

Where does Pilocarpine act and what does it treat?

A

Muscarinic receptors - agonist

Treats glaucoma

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13
Q

Where does oxotremorine act and what does it treat?

A

Muscarinic receptors - agonist

Potential Alzheimers treatment

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14
Q

What receptor agonists are used in the treatment of myasthenia gravis?

A

Nicotinic agonists

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15
Q

What drug is used as an aid to stop smoking?

A

Varenicline

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16
Q

Where does R-Salbutamol act and what does it treat?

A

Adrenergic B2 receptor - agonist

Treats asthma

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17
Q

What is the main structural difference between R-Salbutamol and R-Soterenol?

A

R-Soterenol contains sulphonamide FG

R-Salbutamol contains hydroxymethylene FG instead

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18
Q

Give an example of an opioid analgesic - what’s its use and risks?

A

Morphine - potent analgesic and sedative

Risks of addiction, tolerance and respiratory depression

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19
Q

Where does morphine act? What does it activate?

A

Opioid receptor - G-protein coupled receptor activating Gi or Go signal proteins

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20
Q

Give an example of an allosteric modulator for a G-protein coupled receptor

A

Cinacalcet

(Calcium-sensing receptor)

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21
Q

What does cinacalcet treat?

A

Thyroid problems

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22
Q

What does cinacalcet mimic and hence enhance the action of?

A

Mimics the action of endogenous modulators and enhances the action of the natural chemical messenger.

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23
Q

How are antagonist drugs designed to cause no receptor activation?

A

The drug is a perfect fit - no induced fit

Use of extra binding sites - result in an induced fit that doesn’t activate the receptor
- designed molecule also binds more strongly & prevents natural messenger binding

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24
Q

Give 3 modern techniques used to determine the binding site layout

A

Genetic engineering - change receptors

X-ray crystallography

Computer based molecular modelling

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25
Q

What is estradiol and what’s its affect?

A

Steroid hormone

Affects growth and development of a number of tissues

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26
Q

What factor can be exploited in the estrogen receptor?

A

Very spacious binding pocket - except for region where phenol binds

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27
Q

Once estradiol binds, what proceeds?

A

H12 lid closes and dimerisation occurs - exposing AF-2 regions

Co-activator binds and transcription begins

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28
Q

How does raloxifene act as an antagonist of the estrogen receptor?

A

Long side chain blocking Leu540 from coming in

Protonated amino group on side chain forms H-bond to Asp-351 - protrudes from binding site stopping H12 lid closing in

29
Q

What does raloxifene treat?

A

Hormone dependent breast cancer

30
Q

What are serotonin antagonists used as?

A

CNS active drugs

31
Q

What are adrenergic antagonists used to treat?

A

Cardiovascular medicine - beta blockers

32
Q

What do histamine H2 antagonists treat?

A

Peptide ulcers and hay-fever

33
Q

What do estrogen receptor antagonists treat?

A

Horomone dependent breast cancer

34
Q

What drug treats ulcers and how does it achieve this?

A

Cimetidine - H2 antagonist exploiting extra binding sites

35
Q

Name one a beta blocker, what does it treat and where do they act?

A

S-Metoprolol -2
S-Betaxolol -2
S-Acebutolol -1
S-Atenolol -1

Treats angina and hypertension - B1 receptors prominent in heart

36
Q

Where do antidepressants act and how do they work?

A

At serotonin receptor 5-HT7
-believed to be involved in negative feedback for serotonin release, increasing serotonin levels.

37
Q

What is the importance of the chlorophenoxy group in serotonin antagonists?

A

Improves passing blood-brain barrier

Prevents metabolism

38
Q

What functional groups are key for serotonin antagonists?

A

Naphthalene ring

Sulphonamide group

Piperidine ring

39
Q

Name a cholinergic antagonist

A

Tubocurine

40
Q

What does tubocurarine do and how does it achieve this?

A

Muscle relaxant - blocks nerve transmission from nerve to muscle

41
Q

What is a more unorthodox use of tubocurarine?

A

Used on arrow heads

42
Q

How does tubocurarine lock in to the cholinergic receptor?

A

By binding to acetylcholine site and a nearby cysteine residue.

Two positively charged nitrogens are key in binding.

43
Q

How do allosteric modulators work?

A

By binding to an allosteric binding site, causing a conformational change in the active site - shutting it

44
Q

What is the ‘umbrella’ effect?

A

Large antagonist molecule binds to a neighbouring binding site, blocking the active site form the messenger.

45
Q

What 3 explanations can be given to partial agonists?

A

Ex 1 - agonist may not be causing the IDEAL conformational change, hence receptor effects are reduced

Ex 2 - partial agonist may bind in TWO DIFFERENT WAYS, one way is agonistic and other is antagonistic.

Ex 3 - receptors that bind the same messenger are NOT ALL THE SAME. Partial agonist may be able to distinguish between different receptor types and subtypes

46
Q

What groups decrease agonism and increase antagonism?

A

Methyl

Ethyl

Propyl

47
Q

What group has no agonistic or antagonistic effect on a molecule?

A

Butyl

48
Q

What groups increase agonism?

A

Pentyl and hexyl

49
Q

What opioid analgesic has 14x the activity of morphine and why?

A

N-Phenethylmorphine - benzene extension on side chain

(Additional pockets)

50
Q

Name a partial histamine receptor antagonist

A

N alpha - Guanylhistamine

(Can reach both binding sites due to size)

51
Q

What is an inverse agonist?

A

An inverse agonist is capable of preventing inherent activity of a receptor as well as acting as an antagonist.

52
Q

What does the existence of inverse agonists suggest?

A

That receptors don’t have ‘fixed’ inactive conformations but are continually changing shape.

That there is an equilibrium between the active and inactive conformations

53
Q

What receptors have inherent activity even in the absence of neurotransmitters?

A

GABA and Serotonin

54
Q

How can desensitisation occur?

A

When an agonist binds strongly causing prolonged binging and exposure, so cell reduces synthesis of receptors.

The longer exposure can then cause endocyotsis, where the receptor/drug complex is removed completely from membrane

Phosphorylation can also happen, altering the receptor shape - closing it more permanently

55
Q

Why is desensitisation a problem?

A

More drug is required to have same effect - toxicity issues

56
Q

How does sensitisation occur?

A

Antagonist is slow to add and slow to leave

Cells synthesise more receptors to compensate for the blocked receptors - known to happen with some Beta blockers

57
Q

Define tolerance

A

Higher levels of drug are required to have the same biological response

58
Q

Define dependence

A

When a drug is stopped suddenly - withdrawal symptoms - patient tales drug again to stop symptoms

59
Q

Give an example for both agonist and antagonist therapies for choliergic receptors

A

Agonist - glaucoma (M)

Antagonist - neuromuscular blockers and muscle relaxants (N)

60
Q

Give an example of agonist and antagonist therapies for adrenergic receptors

A

Agonist - anti-asthmatics (B2)

Antagonist - Beta blockers (B1)

61
Q

Give an example of agonist and antagonist therapies for dopamine receptors

A

Agonist - Parkinson’s disease

Antagonist - antidepressants (D2/D3)

62
Q

Give an example of agonist and antagonist therapies for histamine receptors

A

Agonist - vasodilation

Antagonist - allergies (H1) and anti-ulcer (H2)

63
Q

Give an example of agonist and antagonist therapies for 5-Hydroxytryptamine receptors

A

Agonist - anti-migraine (5-HT1D)

Antagonist - anti-depressants (5-HT7)

64
Q

Name one dopamine receptor antagonist and give its use.

A

Clozapine
Olanzapine
Risperidone

All clinically effective antipsychotic agents

65
Q

At what sites do antipsychotic drugs act at? Which is better and why?

A

Act at D2 and D3 receptors

Blockage of D2 receptors - side effects

D3 antagonists generally have better properties as antipsychotic drugs

66
Q

Define affinity - and how is it determined?

A

A measure of how strongly a drug binds to the receptor

Determined by radioligand labelling with a known antagonist

67
Q

Define efficacy - and how is it determined?

A

A measure of the maximum biological effect that a drug can produce as a result of a receptor binding.

Determined by measuring the concentration of drug required to produce 50% of maximum possible effect (EC50)

68
Q

Define potency

A

The amount of drug required to achieve a defined biological effect

CHEM141 (12 decks)

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