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Pharm > Receptors / Dose Response > Flashcards

Receptors / Dose Response Flashcards

1
Q

Ligands

A

Molecules bound by receptors

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2
Q

Agonist

A

Molecule that binds receptor —> produces biological response

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3
Q

Antagonist

A

Molecule that binds a receptor but does not induce a biological response (endogenous mediators blocked)

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4
Q

Characteristics of a receptor

A

Saturability
Specificity
Reversibility
Bifunctional role

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5
Q

Classes of receptors

A

Ion channel receptors
G-protein coupled receptors
Tyrosine kinase receptors
Transcription factor receptors

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6
Q

Examples of ion channel receptors

A

Neurotransmitter receptors (e.g., acetylcholine, GABA, Aspartate, glycine)

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7
Q

Characteristic of ion channel receptors

A

Very fast (millisecond)

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8
Q

Examples of G-protein coupled receptors

A

Neurotransmitters, peptide hormones, biogenic amines

40-50% of pharmaceutical targets are GPCRs

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9
Q

Characteristics of GPCRs

A

G-protein - transducing agent that couples active receptor to cellular response; binds GTP then uncouples from activated receptor

Fast 100s of ms to second

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10
Q

Receptor pathways

A

Receptor to activate and/or inhibit pathway

Receptor can act on / activate multiple pathways

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11
Q

Pathways of GPCRs

A

GPCRs can link to more than one G-protein

GPCRs may initiate cell signaling not traditionally associated with G-proteins

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12
Q

Examples of tyrosine kinase receptors

A

Receptor for insulin, growth factors

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13
Q

Characteristics of tyrosine kinase receptor

A

Slower action - order of minutes

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14
Q

Transcription factor receptors

A

Receptors for steroids, thyroid hormone, vit D, retinoids

Intracellular receptor —> agonists must be hydrophobic to pass through the membrane and bind

Very slow - hours to days

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15
Q

Rate of receptor classes

A

Ion channel > GPCR > tyrosine kinase > transcription factor

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16
Q

Receptor subtypes

A

May have differential distribution —> can exploit for tissue specificity

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17
Q

Receptor affinity

A

ratio of off rate of a ligand binding a receptor to on rate (dissociation constant, Kd)

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18
Q

High affinity

A

Very slow off rate

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19
Q

Lower affinity

A

Faster off rate

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20
Q

No affinity

A

No on rate

21
Q

Saturation isotherm

A

Directly measures binding of a radio labeled ligand to receptor

22
Q

Competition binding assay

A

Compares ability of nonradioactive ligands to compete with radioligand to bind to a receptor

23
Q

Measuring total binding

A
  1. combine tissue + radiolabeled drug
  2. Incubate
  3. Wash off unbound drug
  4. Measure radioactivity
24
Q

Total binding curve

A

Binding experiment done with the same amount of tissue in each tube but with INCREASING conc of radioligand

Aka saturation isotherm

25
Q

Measuring non-specific binding

A
  1. Combine tissue + radiolabeled drug + excess of non-radioactive competing ligand
  2. Incubate
  3. Wash off unbound drug
  4. Measure radioactivity
26
Q

Non-specific binding curve

A

Binding experiment the same as for the total binding curve, but in the presence of high does of competing non-radioactivity ligand

Used to correct the total curve to get the specific binding curve

27
Q

Plateau of the binding curve represents

A

Saturability

28
Q

A lower Kd corresponds to a _____ receptor affinity

A

Higher

29
Q

Kd

A

Concentration of ligand where half maximal binding is obtained

30
Q

Competition binding analysis

A

Measure of % specific radioligand binding relative to increasing concentration of competitor

31
Q

IC50 in competition binding analysis

A

Concentration of competitor which inhibits binding by 50%

32
Q

Lower IC50 in competition binding analysis means …

A

The competitor has a higher receptor affinity

33
Q

Dose response curves

A

Linear plot - hemiparabolic with plateau at saturation; proportional to receptors occupied

Semi log plot - used to be able to display a wider range of doses; sigmoid shape

34
Q

Dose-response curve of antagonist / non-binder

A

Flat line on semi log curve

35
Q

Dose response curves of agonists

A

Sigmoid shape

EC50 - concentration with half-maximal response

Lower EC50 —> more potent agonist

36
Q

Dose-response curve for partial agonist

A

Fails to reach full response (i.e. doesn’t reach saturation point of full agonist)

37
Q

Intrinsic efficacy

A

Ability of ligands to activate receptors

Full agonists - max response; intrinsic efficacy = 1
Partial agonist - less than maximal; 0 < intrinsic efficacy < 1
Antagonist - no response, intrinsic efficacy = 0

38
Q

Molecular basis of intrinsic efficacy

A

Full agonist: full activation of receptor (i.e. binding + full interaction with activation domain)

Partial agonist: partial activation of receptor (i.e. binding + partial interaction with activation domain)

Antagonist: no response (i.e. binds receptor but not activation domain)

39
Q

Potency of a ligand is determined by …

A

Fractional occupancy (binding)
+
Intrinsic efficacy (ability to activate)

40
Q

Effect of competitive antagonist on dose response curve

A

Pretreatment with competitive antagonist directly blocks binding, but with high enough agonist concentration will be displaced

Curve shifts to the right (need higher conc to reach saturation)

41
Q

Effect of non competitive antagonist on dose-response curve

A

Non-competitive antagonist doesn’t block binding of agonist, but prevents subsequent activity upon binding

With antagonist pre-treatment, will need a higher conc to illicit activity, but also will not reach maximum

Dose response curve shifts right and downward

42
Q

Inverse agonist

A

Binds and induces a biological response in the opposite direction of an agonist

43
Q

Other factors impacting the biological response

A

Spare receptors - shift does response curve left
(Greater response despite equivalent concentration of agonist - % receptors bound is the same, but the overall # bound is higher)

Large threshold for response - shift curve right

44
Q

Receptor desensitization

A

Receptor can still bind agonist, but cell signaling is disrupted

45
Q

Receptor downregulation

A

Receptor pulled off cell surface

46
Q

Drug tolerance develops in response to

A

Receptor desensitization
Receptor downregulation

Elongates/flattens out the slope of the dose response curve (down/right shift)

47
Q

Drug vacation

A

When receptor desensitization / downregulation occur; switch to a medication that acts by a DIFFERENT pathway to allow original pathway to resensitize

48
Q

Receptor supersensitivity

A

Response following denervation —> nerve dies —> upregulation of receptors that make tissue supersensitive to any neurotransmitter

Pharm (10 decks)

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