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DDD x > Week 1 Part 2 > Flashcards

Week 1 Part 2 Flashcards

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1
Q

What are some clinically useful partial agonist?

A
  1. Buprenorphine

2. Varenicline

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2
Q

Define ligand

A

any chemical which combines with a receptor

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3
Q

Ligand binds to recognition site of receptor

A
  1. agonist bind to recognition site

2. change conformation - opening/closing of relevant ion channel

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4
Q

What is the direction of ion movement dependent on?

A

concentration/electrochemical gradient

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5
Q

What happens to the target cell?

A

nature of the ion

not all ion channels are created equal

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6
Q

sodium floods in

A

depolarisation

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7
Q

chloride floods in

A

hyperpolarisation

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8
Q

Define affinity

A

Tenacity by which a drug binds to its receptor

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9
Q

What does ligands reside at?

A

minimal energy within a binding locus of a protein

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10
Q

What is the binding affinity influenced by?

A

non-covalent intermolecular interactions

e. g.
1. Hydrogen bonding
2. Electrostatic interactions
3. Hydrophobic and van der waal forces between 2 molecules

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11
Q

The higher the affinity

A

The lower this concentration will be

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12
Q

What is binding affinity measured and reported by?

A

Equilibrium dissociation

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13
Q

What is equilibrium dissociation used for?

A

Evaluate and rank order strengths of bimolecular interactions

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14
Q

The smaller the KD value

A

The greater the binding affinity of ligand for its target

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15
Q

What is KD?

A

a constant between free drug conc and free receptor conc

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16
Q

What happens if you increase the conc of drug?

A
  1. shift equilibrium over to right

2. increase in drug-receptor complex

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17
Q

What is the equation for KD?

A

Free drug [D] + unbound receptor [R] divided by drug-receptor associated complex [DR]

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18
Q

What yields a low KD value?

A

The numerator of equation will be low

The denominator will be high

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19
Q

Define antagonist

A

Blocks or dampens a biological response by binding to and blocking a receptor

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20
Q

Define agonist

A

A ligand that binds to receptor and alters receptor site - result in a biological response

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21
Q

What can receptor antagonist be?

A
  1. Competitive
  2. Non-competitive
  3. Reversible
  4. Irreversible
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22
Q

What is a reversible antagonist?

A

Binds non-covalently to the receptor

Can be washed out

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23
Q

What is irreversible antagonist

A

Bind covalently to the receptor and cannot be displaced by either competing ligands or washing

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24
Q

What is competitive antagonist?

A

Bind to the same site as agonist and blocks the agonists action

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25
What is non-competitive antagonist?
Bind to allosteric site on the receptor to prevent activation of receptor
26
What is example of competitive antagonist?
1. simple competitive e.g. nanitidine | 2. Pseudo-irreversible slowly dissociating e.g. alosetron
27
What is example of non-competitive?
1. Irreversible: chemically modifies receptor e.g. phenoxy-benzamine 2. Allosteric e.g. b-carbolines (BDZ receptor) 3. Functionl: acts as a second receptor
28
What are examples of clinically useful reversible competitive antagonist?
1. Ondansetron 2. Carvedilol 3. Naloxone
29
What is used to block endogenous agonist?
1. Ondansetron (Zofran) | 2. Carvedilol (Eucardic)
30
What is Ondansetron?
1. HT-3 receptor reversible competitive antagonist | 2. inhibit vomitting
31
What is Carvedilol?
1. Beta1 selective adrenoceptor reversible competive antagonist 2. treatment of hypertension
32
What is used to block exogenous agonist?
1. Naloxone 2. opioid receptor competitive antagonist 3. reverse opioid induced respiratory depression/overdose
33
What is EC50?
drug concentration producing 50% of a maximal effect
34
When is there an equilbrium?
Agonist and antagonist competing for a target site
35
What can restore agonist occupancy?
Raising agonist concentration
36
What happens when there is an increased agonist concentration?
1. increase in fractional occupancy | 2. magnitude of functional response is seen
37
What doesnt antagonist have?
efficacy - need a suitable agonist - action can be inhibited by the antagonist of interest
38
What can antagonist potency be expressed in?
PA2 value
39
Define PA2?
Negative logarithm of molar concentation of antagonist which will reduce the response of a tissue
40
What is an advantage of non-competitive inhibitor?
Duration of action is dependent on the rate of turnover of receptor molecules
41
What is disadvantage of non-competitive inhibitors?
Overdose
42
What is H+/K+ ATPase?
Proton pump of the stomach Exchanges H+ for K
43
Where is H+/K+ ATPase found?
Apical membrane of parietal cells
44
What is parietal cells?
Highly specialised epithelial cells located in inner lining of stomach called gastric mucosa
45
How is H+/K+ ATPase activated?
Indirectly by gastrin that causes ECL cells to release histamine
46
What does histamine do?
Bind to H2 receptors on the parietal cells Activate CAMP-dependent pathway
47
Where is K+ recycled from?
Canaliculus (small passageway) into the cytoplasm by K+ channels in apical membrane
48
Describe mode of action of Omeprazole?
1. Absorbed by GI tract into blood 2. At PH7 omeprazole is not charged and can cross cell membrane 3. In acid enviroment of secretory canaliculus - omeprazole is protonated and therefore trapped so concentration increases 4. Omeprazole inactive on protonation converts to active sulfenamide - reacts convalently with H+/K+ ATPase and inhibits activity 5. Resumption of acid secretion requires new synthesis of H+/K+ ATPase 6. Half life of Omeprazole is ~18 hours
49
What does G protein bind to?
guanine nucleotide GDP and GTP
50
What are the 3 different subunits associated with inner surface of plasma membrane and transmembrane receptors?
1. Ga 2. GB 3. GY
51
What happens in the inactive state?
Ga has GDP in its binding site
52
What happens when a hormone or other ligand bind to associated GPCR?
Allosteric change takes place in the receptor causes allosteric change in Ga causing GDP to leave and be replaced by GTP
53
What does GTP activate?
GA causing it to dissociate from GbGY
54
What does activated Ga activate?
Effector molecule
55
what does morphine mimic?
Endogenous enkephalin
56
Define potency
The amount of drug required to produce a given effect
57
Define efficacy
The degree to which an agonist evokes a cellular response
58
What does intrinsic activity refer to?
Effect of agonist at the receptor itself, rather than overall effect on tissue
59
Define EC50
the molar concentration of an agonist that produces 50% of maximal possible effect of that agonist
60
Define pEC50
the negative logarithm to the base 10 of EC50 of an agonist
61
What is pEC50 useful for?
1. compare potencies of drugs | 2. estimate margin of safety, relative to other actions of drug
62
What does potency depend on?
1. Drug factors - efficacy and affinity | 2. System factors - receptor number and efficiency of coupling
63
What can system factors cancel out?
Differences in drug factors
64
What happens as the concentration of drug is increased?
Full agonist will go up to 100%
65
What does partial agonist have?
1. Affinity for receptor | 2. Low efficacy
66
What will partial agonist not produce?
maximum respinse has efficacy of less than 1
67
What can partial agonist reduce?
apparent Emax
68
What are some examples of clinically useful partial agonist?
1. Buprenorphine (Subutex) | 2. Varenicline (Champix)
69
What is Buprenorphine?
1. Opioid receptor partial agonist 2. produces pain relief with lower risk of respiratory depression 3. used in situation of drug overdose and/or opioid abuse
70
What is Varenicline?
1. Alpha4/beta 2 selective nicotinic receptor partial agonist 2. treat nicotine dependence
71
What is inverse agonist?
Agent that binds to same receptor as agonist but induces a pharmacological response opposite to that of agonist
72
What can the effect of inverse agonist be blocked by?
antagonist
73
What must the receptor of inverse agonist have?
Constitutive activity in absence of ligand
74
What does inverse agonist do?
Decrease the activity of a receptor below basal level
75
What is the efficacy of inverse agonist?
<0%
76
What does inverse agonist do?
1. have higher affinity for the active state of receptor | 2. shift the equilibrium back to inactive state
77
What is constitutive activity?
A receptor which is capable of producing a biological response in the absence of bound ligand
78
What is inverse agonist capable of doing?
Block constitutive activity of a receptor
79
What is activation of G protein coupled receptors
1. Activation of G proteins 2. Receptor phosphorylation by GRKS 3. B-arrestin migrates to receptor on activation 4. leads to receptor internalisation into endosomes 5. Internalised receptor/ B arrestin complex forms a scaffold MAP kinases to produce signal in cytosol 6. Internalised receptor recycles to cell surface or degraded
80
What is biased agonism?
Ligand-dependent selectivity for certain signal transduction pathways relative to a reference ligand
81
When is functional selectivity present?
When a receptor has several possible signal transduction pathways
82
Where is functional selectivity most extensively characterised?
GPCR
83
What can receptors be seen to do?
Transverse an ''energy landscape' thermal energy drives the protein into preferred energy wells
84
What happens when a molecule bind to receptor?
It becomes another thermodynamic species
85
What are receptor confirmations?
Interconvertible
86
What is Le Chatelier's principle?
If a dynamic equilibrium is disturbed by changing the conditions, the position of equilibirum moves to counteract change
87
What does a ligand enrich?
A particular confirmation that exist in accordance with thermal energy in system and proteins exist in ''ensembles'' of multiple conformations
88
What does morphine do?
Activates the mu opioid receptor, a GPCR
89
What is TRV130?
A G protein-biased ligand elicits a robust G protein signalling with potency and efficacy similar to morphine
90
What is TRV130 suggested to be?
Safer and more tolerable therapeutic for treating severe pain

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