Receptor Theory and Dose-Response Relationships

Question 1

receptor

Answer 1

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

Question 2

macromoleucles that can be receptors

Answer 2

cell surface or intracellular regulatory proteins

enzymes

structural proteins

nucleic acids

Question 3

primary types of receptors

Answer 3

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

Question 4

two general features of receptors

Answer 4

recognition site and transduction mechanism

Question 5

How are receptors described

Answer 5

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

Question 6

basic principles of “receptor theory”

Answer 6

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

determine drug selectivity

mediate the actions of pharmacological agonists and antagonists

Question 7

four main categories of drugs

Answer 7

agonists

antagonists

partial agonists

inverse agonists

Question 8

agonists

Answer 8

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

often agonists mimic the activity of endogenous molecules

Question 9

antagonists

Answer 9

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

Question 10

partial agonists

Answer 10

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)

Question 11

inverse agonists

Answer 11

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

Question 12

carbamylcholine

Answer 12

agonist at ACh receptors

Question 13

atropine

Answer 13

binds to, but does not activate, ACh receptors

binding prevents ACh binding

thus is an agonist of the receptor

Question 14

oxotremorine

Answer 14

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

oxotremorine is a partial agonist

Question 15

different types of antagonism

Answer 15

chemical

physiological

pharmacological

Question 16

chemical antagonism

Answer 16

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

Question 17

physiological antagonism

Answer 17

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

Question 18

pharmacological antagonism

Answer 18

ligands that bind but do not activate receptors

Question 19

positive allosterism

Answer 19

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)

Question 20

negative allosterism

Answer 20

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

Question 21

noncompetitive allosteric site

Answer 21

a stie that is accessible in the absence of agonist

Question 22

uncompetitive allosteric site

Answer 22

requires receptor activation before it becomes accessible to a drug

Question 23

ligand-receptor selectivity

Answer 23

closely related analogs have different activities on different sets of receptors

ex. adenine modifications have very distinct effects

Question 24

factors that contribute to the selectivity of a drug

Answer 24

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

Question 25

What features define the pharmacological properties of a drug

Answer 25

chemistry, cellular distribution, and pharmacokinetic properties

Question 26

general equation describing drug action

Answer 26

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

Question 27

law of mass action

Answer 27

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

Question 28

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

Answer 28

EC50 or ED50 is the concentration that yields 50% of maximum response **quantification of drug activity**

Question 29

Describe the equation and graph for ligand binding kinetics.

Answer 29

KD is the concentration at which 50% of receptors are occupied **quantitation of binding affinity**

Question 30

potency

Answer 30

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

Question 31

efficacy

Answer 31

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

Question 32

graded dose-response

Answer 32

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

Question 33

quantal dose-response

Answer 33

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

Question 34

therapeutic index

Answer 34

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"

Question 35

pharmacogenomics

Answer 35

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

Question 36

competitive antagonist

Answer 36

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

Question 37

equation that describes competitive antagonists

Answer 37

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

Question 38

noncompetitive antagonists

Answer 38

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

Question 39

inhibition-response curves

Answer 39

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

Question 40

Schild Analysis

Answer 40

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

Question 41

functional antagonism with partial agonists

Answer 41

partial agonists bind to the same site as full agonists but are less efficacious effectively reduce maximal response through competition for the binding site

Question 42

coupling

Answer 42

the transduction process between receptor binding and biological effect

Question 43

spare receptors

Answer 43

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

Question 44

inverse agonists

Answer 44

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

Question 45

Monod-Wyman-Changeaux model

Answer 45

postulated that receptors exist in equillibrium between two conformational states that wre differentially stabilized by pharmacological compounds model proven to be incorrect

Question 46

Koshland-Nemethy-Filmer model

Answer 46

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

Question 47

What receptor is most commonly targeted by drugs?

Answer 47

Rhodopsin-like GPCRs

Question 48

four receptor superfamilies

Answer 48

intracellular receptors transmembrane proteins with intrinsic or auxillary enzymatic activities ligand- or voltage-gated ion channels G-protein coupled receptors

Question 49

intracellular receptors

Answer 49

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

Question 50

six families of intracellular receptors

Answer 50

thyroid hormone receptor-like retinoid C receptor-like estrogen receptor-like nerve growth factor 1B-like steroidogenic factor-like germ cell nuclear factor-like

Question 51

tamoxifen

Answer 51

partial agonist that acts as an atagonist blocks recruitment of coregulators can also be a prodrug when metabolized

Question 52

enzyme-linked receptors

Answer 52

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

Question 53

six families of enzyme-linked receptors

Answer 53

receptor tyrosine kinases (RTKs) tyrosine kinase-associated receptors receptor like tyrosine phosphatases receptor serine/threonine kinases receptor guanylyl kinases histidine-kinase-associated receptors

Question 54

receptor tyrosine kinases

Answer 54

many growth factors are ligands dimerization required for activation other signaling molecules can bind to RTKs central role in many cancers

Question 55

tyrosine kinase-associated receptors

Answer 55

cytokines are ligands dimerization required for activation

Question 56

receptor-like tyrosine phosphatases

Answer 56

ligands are unknown remove phosphate groups form signaling proteins

Question 57

receptor serine/threonine kinases

Answer 57

TGF-beta, BMP, and activin are ligands phosphorylate serines and threonines on gene regulatory molecules

Question 58

receptor guanylyl kinases

Answer 58

natriuretic peptides are ligands catalyze production of cGMP, which acts as a signaling molecule

Question 59

histidine-kinase-associated receptors

Answer 59

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

Question 60

activation of RTKs

Answer 60

ligand binds to extracellular domain binding induces dimerization kinase domain autophosphorylates tyrosine residues activate numerous and complex signaling pathways

Question 61

ligand- and voltage-gated ion channels

Answer 61

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

Question 62

three super0families of ligand-gated ion channels

Answer 62

cys-loop receptors ionotropic glutamate receptors ionotropic ATP receptors

Question 63

cys-loop receptors

Answer 63

pentameric (five component subunits) GABA, GABAc receptors glycine receptors nicotinic ACh receptors Serotonin 5HT3 receptors

Question 64

ionotropic glutamate receptors

Answer 64

tetrameric (four component subunits) AMPA, kainate, and NMDA subtypes

Question 65

ionotropic ATP receptors

Answer 65

trimeric (three component subunits) P2X receptors

Question 66

memantine

Answer 66

one of the only clinically useful NMDA receptor blockers

Question 67

channelopathies

Answer 67

inherited diseases caused by dysfunctional ion channels ex. cystic fibrosis and long QT syndrome

Question 68

G protein-coupled receptors

Answer 68

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

Question 69

three super-families of GPCRs

Answer 69

Family A (rhodopsin-like) Family B (secretin-like) Family C (metabotropic) (also the Frizzled family - Wnt)

Question 70

Class A: rhodopsin-like GPCRs

Answer 70

rhodopsin biogenic amine receptors olfactory receptors

Question 71

Class B: secretin-like GPCRs

Answer 71

gastrointestinal peptides CRH

Question 72

Class C: metabotropic

Answer 72

mGluRs GABA(B)Rs calcium-sensing receptors

Question 73

ionotropic vs. metabotropic receptors rate of response

Answer 73

ionotropic receptors are on a millisecond timescale metabotropic are on a second timescale

Question 74

non-canonical GPCR signaling

Answer 74

beta arrestin binds and becomes a scaffold for other proteins

Question 75

GPCR dimerization

Answer 75

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

Question 76

beta-arrestin

Answer 76

scaffolding function and also necessary to internalize active GPCRs

Question 77

tachyphylaxis

Answer 77

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

Question 78

receptor-mediated desensitization

Answer 78

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

Question 79

non-receptor-mediated desensitization

Answer 79

decoupling downstream elements required for signaling reduction in drug concentration physiological adaptaion

Question 80

two major class of receptors that have acetylcholine as a ligand

Answer 80

nicotinic acetylcholine and muscarinic acetylcholine receptors an example of two very different receptor subtypes