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Foundations 2 > Receptor Theory and Dose-Response Relationships > Flashcards

Receptor Theory and Dose-Response Relationships Flashcards

1
Q

receptor

A

the component of a cell or organism that ineracts with a drug and initiates the chain of biochemical events leading to the drug’s observed effects

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2
Q

macromoleucles that can be receptors

A

cell surface or intracellular regulatory proteins

enzymes

structural proteins

nucleic acids

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3
Q

primary types of receptors

A

intracellular receptor that binds a lipophilic drug

transmembrane receptor with intrinsic enzyme activity

transmembrane receptor with auxiliary enzyme

ligand- or voltage-gated ion channel

G-protein coupled receptor

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4
Q

two general features of receptors

A

recognition site and transduction mechanism

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5
Q

How are receptors described

A

pharmacalogically based on their activating ligands as wel las genetically based on genetic composition

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6
Q

basic principles of “receptor theory”

A

largely determine the quantitative relations between a drug and its pharmacological effects

determine drug selectivity

mediate the actions of pharmacological agonists and antagonists

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7
Q

four main categories of drugs

A

agonists

antagonists

partial agonists

inverse agonists

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8
Q

agonists

A

drugs that interact directly with their receptors to produce a biological response

often agonists mimic the activity of endogenous molecules

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9
Q

antagonists

A

drugs that bind to receptors but which do not directly produce a biological response

antagonists inhibit the action of endogenous or synthetic agonists

active site and allosteric site agonists

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10
Q

partial agonists

A

elicit less than the maximal response from the receptor

can also be used to prevent maximal activation by full agonists (a form of funcitonal antagonism)

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11
Q

inverse agonists

A

actually are antagonists that reduce the activity of a constitutively active receptor

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12
Q

carbamylcholine

A

agonist at ACh receptors

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13
Q

atropine

A

binds to, but does not activate, ACh receptors

binding prevents ACh binding

thus is an agonist of the receptor

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14
Q

oxotremorine

A

partially mimics the effects of ACh in some system, but it does not produce the same maximal response

oxotremorine is a partial agonist

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15
Q

different types of antagonism

A

chemical

physiological

pharmacological

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16
Q

chemical antagonism

A

inactivation of one drug by the direct binding or interaction of another drug

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17
Q

physiological antagonism

A

application of a drug to elicit physiological responses that counteract the actions of another drug

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18
Q

pharmacological antagonism

A

ligands that bind but do not activate receptors

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19
Q

positive allosterism

A

enhances agonist-mediated responses from the receptor through binding to a site distinct from that occupied by agonists

do not independently activate the receptor (in absence of agonist)

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20
Q

negative allosterism

A

agonist-dependent - reduce agonist-evoked signaling from an allosteric site

agonist-independent - “inverse agonists” reduce receptor function in both the absence and presence of agonist

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21
Q

noncompetitive allosteric site

A

a stie that is accessible in the absence of agonist

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22
Q

uncompetitive allosteric site

A

requires receptor activation before it becomes accessible to a drug

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23
Q

ligand-receptor selectivity

A

closely related analogs have different activities on different sets of receptors

ex. adenine modifications have very distinct effects

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24
Q

factors that contribute to the selectivity of a drug

A

receptor distribution - drugs act on those tissues, cells, or synapses that express their receptors

pharmacokinetics - drugs differ in their chemical structure, which influences their bioavailability to different compartments and their metabolism

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25
Q

What features define the pharmacological properties of a drug

A

chemistry, cellular distribution, and pharmacokinetic properties

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26
Q

general equation describing drug action

A

drug (D) + receptor (R) <—> [Drug-Receptor (DR) complex] <—> Effect

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27
Q

law of mass action

A

the rate of a chemical reaction is directly proportional to the product of the effective concentrations of each participating molecule

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28
Q

Describe the dose-response relationship for a drug. Also state the equation.

A

EC50 or ED50 is the concentration that yields 50% of maximum response

quantification of drug activity

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29
Q

Describe the equation and graph for ligand binding kinetics.

A

KD is the concentration at which 50% of receptors are occupied

quantitation of binding affinity

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30
Q

potency

A

a comparative measure of the concentration of drugs that produce a given relative effect

usually used to compare different drugs

depends on the binding affinity and coupling efficiency of a drug

relative tomaxiumum effect produced by each drug

Drug A is more potent than B but equipotent to C

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31
Q

efficacy

A

a measure of maximal effectivenes sof a drug

partial agonists exhibit less than maximal efficacy

agonists have no efficacy

Drug A and B are full agonists whereas C is a partial agonist

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32
Q

graded dose-response

A

a quantitative curve that relates the dose of a drug to a quantitatively graded effect

as dose increases, the effect of the drug increases, and at a maximum point, an effect ceiling is achieved

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33
Q

quantal dose-response

A

descrube the frequency with wich an all-or–none response occurs in a specified population

required to produce a specific effect in one person

response is not graded but rather present or absent

expressed as cumulative percent or fraction or as frequency distribution

ED50 is the mean effective dose at which 50% of individuals exhibit the specified effect

34
Q

therapeutic index

A

toxic ED50/beneficial ED50

1 or lower is a dangerous drug, whereas higher numbers are better

primary goal of therapy is to use drugs that are as specific as possible and avoid “side effects”

35
Q

pharmacogenomics

A

study of the impact of genetically-encoded variation on responses to drugs

36
Q

competitive antagonist

A

drugs that bind reversibly to the same binding site as the agonist

increasing concentrations of agonist can overcome effects of the antagonist

will shift the dose-response curve to the right in a parallel manner

efficacy of the agonist will not be reduced, but the potecny will be affected

37
Q

equation that describes competitive antagonists

A

measured effect depends on the concentration of both the agonist and the competitive agonist

38
Q

noncompetitive antagonists

A

bind irreversibly to the same site as agonist or a distinct allosteric site on the receptor

reduces function, and increasing concentration of agonist does not overcome the effect of the antagonist

depression of effect max in the DR curve, but potency is unchanged

39
Q

inhibition-response curves

A

increase the amount of agonist at a fixed concentration of agonist to derive an IC50 value, will vary depending on the concentratino of agonist

can only be used for agonist-dependent interactions

40
Q

Schild Analysis

A

provides an agonst-independent equilibrium constant for agonist-receptor interactions

41
Q

functional antagonism with partial agonists

A

partial agonists bind to the same site as full agonists but are less efficacious

effectively reduce maximal response through competition for the binding site

42
Q

coupling

A

the transduction process between receptor binding and biological effect

43
Q

spare receptors

A

sometimes the full response of an agonist may be generated by occupation of only a small percentage of the available population of receptors

the dose response curves tend to fall to the right of those for drug response

this is not observed with ligand-gated ion channels because the receptor directly produces the effect

44
Q

inverse agonists

A

drugs that reduce the activity of a constitutively active receptor

many G protein-coupled receptors exhibit constitutive activity

antagonists that reduce this activity are said to have negative efficacy

two types - competitive and noncompetitive

45
Q

Monod-Wyman-Changeaux model

A

postulated that receptors exist in equillibrium between two conformational states that wre differentially stabilized by pharmacological compounds

model proven to be incorrect

46
Q

Koshland-Nemethy-Filmer model

A

postulated that receptors can undergo sequential alterations to a multiple of potential conformations that differ when full agonists, partial agonists, or antagonists are bound

47
Q

What receptor is most commonly targeted by drugs?

A

Rhodopsin-like GPCRs

48
Q

four receptor superfamilies

A

intracellular receptors

transmembrane proteins with intrinsic or auxillary enzymatic activities

ligand- or voltage-gated ion channels

G-protein coupled receptors

49
Q

intracellular receptors

A

ligands must be lipophilic to cross plasma membrane

receptors often enter the nucleus after binding ligand and alter gene transcription

six families of intracellular receptors

50
Q

six families of intracellular receptors

A

thyroid hormone receptor-like

retinoid C receptor-like

estrogen receptor-like

nerve growth factor 1B-like

steroidogenic factor-like

germ cell nuclear factor-like

51
Q

tamoxifen

A

partial agonist that acts as an atagonist blocks recruitment of coregulators

can also be a prodrug when metabolized

52
Q

enzyme-linked receptors

A

bind to extracellular signaling proteins

ligands can be diffusible or attached to srufaces that cells contact during movement

signaling response to ligand binding is slow (~hours)

many subsequent intracellular signaling steps that lead to transcriptional changes

enzymatic activity can be intrinsic to receptor or an associated protein

53
Q

six families of enzyme-linked receptors

A

receptor tyrosine kinases (RTKs)

tyrosine kinase-associated receptors

receptor like tyrosine phosphatases

receptor serine/threonine kinases

receptor guanylyl kinases

histidine-kinase-associated receptors

54
Q

receptor tyrosine kinases

A

many growth factors are ligands

dimerization required for activation

other signaling molecules can bind to RTKs

central role in many cancers

55
Q

tyrosine kinase-associated receptors

A

cytokines are ligands

dimerization required for activation

56
Q

receptor-like tyrosine phosphatases

A

ligands are unknown

remove phosphate groups form signaling proteins

57
Q

receptor serine/threonine kinases

A

TGF-beta, BMP, and activin are ligands

phosphorylate serines and threonines on gene regulatory molecules

58
Q

receptor guanylyl kinases

A

natriuretic peptides are ligands

catalyze production of cGMP, which acts as a signaling molecule

59
Q

histidine-kinase-associated receptors

A

bacterial chemotaxis

activate a two-component pathway: first phosphorylate itself on a histidine and then transfer the phosphate to a signaling protein

60
Q

activation of RTKs

A

ligand binds to extracellular domain

binding induces dimerization

kinase domain autophosphorylates tyrosine residues

activate numerous and complex signaling pathways

61
Q

ligand- and voltage-gated ion channels

A

receptors contain transmembrane semipermeable channels

ligands are small molecules (neurotransmitters)

voltage channels and mechanical deformation can also activate channels

fast signaling through movement of ions

62
Q

three super0families of ligand-gated ion channels

A

cys-loop receptors

ionotropic glutamate receptors

ionotropic ATP receptors

63
Q

cys-loop receptors

A

pentameric (five component subunits)

GABA, GABAc receptors

glycine receptors

nicotinic ACh receptors

Serotonin 5HT3 receptors

64
Q

ionotropic glutamate receptors

A

tetrameric (four component subunits)

AMPA, kainate, and NMDA subtypes

65
Q

ionotropic ATP receptors

A

trimeric (three component subunits)

P2X receptors

66
Q

memantine

A

one of the only clinically useful NMDA receptor blockers

67
Q

channelopathies

A

inherited diseases caused by dysfunctional ion channels

ex. cystic fibrosis and long QT syndrome

68
Q

G protein-coupled receptors

A

ligands can be small molecules, peptides or proteins

signal over much slower time courses than ion channels

some types (particularly family C) might dimerize

three superfamilies

seven transmembrane domains

69
Q

three super-families of GPCRs

A

Family A (rhodopsin-like)

Family B (secretin-like)

Family C (metabotropic)

(also the Frizzled family - Wnt)

70
Q

Class A: rhodopsin-like GPCRs

A

rhodopsin

biogenic amine receptors

olfactory receptors

71
Q

Class B: secretin-like GPCRs

A

gastrointestinal peptides

CRH

72
Q

Class C: metabotropic

A

mGluRs

GABA(B)Rs

calcium-sensing receptors

73
Q

ionotropic vs. metabotropic receptors rate of response

A

ionotropic receptors are on a millisecond timescale

metabotropic are on a second timescale

74
Q

non-canonical GPCR signaling

A

beta arrestin binds and becomes a scaffold for other proteins

75
Q

GPCR dimerization

A

Activates G proteins coupled to the same receptor - cis activation

Trans activation - activate other G protein in the dimer

Can also have differential activation of the kinases that tend to be associated with GPCRs called GRK (G protein receptor kinase)

Also activation of arrestin pathways

76
Q

beta-arrestin

A

scaffolding function and also necessary to internalize active GPCRs

77
Q

tachyphylaxis

A

drug desensitization

two types: receptor-mediated and non-receptor-mediated

78
Q

receptor-mediated desensitization

A

only the activated receptor desensitizes

loss of function

reduction in number of functional receptors

loss of receptor function can result from negative feedback to receptor or changes in conformational states

reduction in receptor number is a slower process and also due to negative feedback, tightly controlled and regulated

79
Q

non-receptor-mediated desensitization

A

decoupling downstream elements required for signaling

reduction in drug concentration

physiological adaptaion

80
Q

two major class of receptors that have acetylcholine as a ligand

A

nicotinic acetylcholine and muscarinic acetylcholine receptors

an example of two very different receptor subtypes

Foundations 2 (33 decks)

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