Receptor Theory and Dose-Response Relationships Flashcards
receptor
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
macromoleucles that can be receptors
cell surface or intracellular regulatory proteins
enzymes
structural proteins
nucleic acids
primary types of receptors
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
two general features of receptors
recognition site and transduction mechanism
How are receptors described
pharmacalogically based on their activating ligands as wel las genetically based on genetic composition
basic principles of “receptor theory”
largely determine the quantitative relations between a drug and its pharmacological effects
determine drug selectivity
mediate the actions of pharmacological agonists and antagonists
four main categories of drugs
agonists
antagonists
partial agonists
inverse agonists
agonists
drugs that interact directly with their receptors to produce a biological response
often agonists mimic the activity of endogenous molecules
antagonists
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
partial agonists
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)
inverse agonists
actually are antagonists that reduce the activity of a constitutively active receptor
carbamylcholine
agonist at ACh receptors
atropine
binds to, but does not activate, ACh receptors
binding prevents ACh binding
thus is an agonist of the receptor
oxotremorine
partially mimics the effects of ACh in some system, but it does not produce the same maximal response
oxotremorine is a partial agonist
different types of antagonism
chemical
physiological
pharmacological
chemical antagonism
inactivation of one drug by the direct binding or interaction of another drug
physiological antagonism
application of a drug to elicit physiological responses that counteract the actions of another drug
pharmacological antagonism
ligands that bind but do not activate receptors
positive allosterism
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)
negative allosterism
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
noncompetitive allosteric site
a stie that is accessible in the absence of agonist
uncompetitive allosteric site
requires receptor activation before it becomes accessible to a drug
ligand-receptor selectivity
closely related analogs have different activities on different sets of receptors
ex. adenine modifications have very distinct effects
factors that contribute to the selectivity of a drug
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
What features define the pharmacological properties of a drug
chemistry, cellular distribution, and pharmacokinetic properties
general equation describing drug action
drug (D) + receptor (R) <—> [Drug-Receptor (DR) complex] <—> Effect
law of mass action
the rate of a chemical reaction is directly proportional to the product of the effective concentrations of each participating molecule
Describe the dose-response relationship for a drug. Also state the equation.
EC50 or ED50 is the concentration that yields 50% of maximum response
quantification of drug activity
Describe the equation and graph for ligand binding kinetics.
KD is the concentration at which 50% of receptors are occupied
quantitation of binding affinity
potency
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
efficacy
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
graded dose-response
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
quantal dose-response
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
therapeutic index
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”
pharmacogenomics
study of the impact of genetically-encoded variation on responses to drugs
competitive antagonist
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
equation that describes competitive antagonists
measured effect depends on the concentration of both the agonist and the competitive agonist
noncompetitive antagonists
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
inhibition-response curves
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
Schild Analysis
provides an agonst-independent equilibrium constant for agonist-receptor interactions
functional antagonism with partial agonists
partial agonists bind to the same site as full agonists but are less efficacious
effectively reduce maximal response through competition for the binding site
coupling
the transduction process between receptor binding and biological effect
spare receptors
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
inverse agonists
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
Monod-Wyman-Changeaux model
postulated that receptors exist in equillibrium between two conformational states that wre differentially stabilized by pharmacological compounds
model proven to be incorrect
Koshland-Nemethy-Filmer model
postulated that receptors can undergo sequential alterations to a multiple of potential conformations that differ when full agonists, partial agonists, or antagonists are bound
What receptor is most commonly targeted by drugs?
Rhodopsin-like GPCRs
four receptor superfamilies
intracellular receptors
transmembrane proteins with intrinsic or auxillary enzymatic activities
ligand- or voltage-gated ion channels
G-protein coupled receptors
intracellular receptors
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
six families of intracellular receptors
thyroid hormone receptor-like
retinoid C receptor-like
estrogen receptor-like
nerve growth factor 1B-like
steroidogenic factor-like
germ cell nuclear factor-like
tamoxifen
partial agonist that acts as an atagonist blocks recruitment of coregulators
can also be a prodrug when metabolized
enzyme-linked receptors
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
six families of enzyme-linked receptors
receptor tyrosine kinases (RTKs)
tyrosine kinase-associated receptors
receptor like tyrosine phosphatases
receptor serine/threonine kinases
receptor guanylyl kinases
histidine-kinase-associated receptors
receptor tyrosine kinases
many growth factors are ligands
dimerization required for activation
other signaling molecules can bind to RTKs
central role in many cancers
tyrosine kinase-associated receptors
cytokines are ligands
dimerization required for activation
receptor-like tyrosine phosphatases
ligands are unknown
remove phosphate groups form signaling proteins
receptor serine/threonine kinases
TGF-beta, BMP, and activin are ligands
phosphorylate serines and threonines on gene regulatory molecules
receptor guanylyl kinases
natriuretic peptides are ligands
catalyze production of cGMP, which acts as a signaling molecule
histidine-kinase-associated receptors
bacterial chemotaxis
activate a two-component pathway: first phosphorylate itself on a histidine and then transfer the phosphate to a signaling protein
activation of RTKs
ligand binds to extracellular domain
binding induces dimerization
kinase domain autophosphorylates tyrosine residues
activate numerous and complex signaling pathways
ligand- and voltage-gated ion channels
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
three super0families of ligand-gated ion channels
cys-loop receptors
ionotropic glutamate receptors
ionotropic ATP receptors
cys-loop receptors
pentameric (five component subunits)
GABA, GABAc receptors
glycine receptors
nicotinic ACh receptors
Serotonin 5HT3 receptors
ionotropic glutamate receptors
tetrameric (four component subunits)
AMPA, kainate, and NMDA subtypes
ionotropic ATP receptors
trimeric (three component subunits)
P2X receptors
memantine
one of the only clinically useful NMDA receptor blockers
channelopathies
inherited diseases caused by dysfunctional ion channels
ex. cystic fibrosis and long QT syndrome
G protein-coupled receptors
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
three super-families of GPCRs
Family A (rhodopsin-like)
Family B (secretin-like)
Family C (metabotropic)
(also the Frizzled family - Wnt)
Class A: rhodopsin-like GPCRs
rhodopsin
biogenic amine receptors
olfactory receptors
Class B: secretin-like GPCRs
gastrointestinal peptides
CRH
Class C: metabotropic
mGluRs
GABA(B)Rs
calcium-sensing receptors
ionotropic vs. metabotropic receptors rate of response
ionotropic receptors are on a millisecond timescale
metabotropic are on a second timescale
non-canonical GPCR signaling
beta arrestin binds and becomes a scaffold for other proteins
GPCR dimerization
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
beta-arrestin
scaffolding function and also necessary to internalize active GPCRs
tachyphylaxis
drug desensitization
two types: receptor-mediated and non-receptor-mediated
receptor-mediated desensitization
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
non-receptor-mediated desensitization
decoupling downstream elements required for signaling
reduction in drug concentration
physiological adaptaion
two major class of receptors that have acetylcholine as a ligand
nicotinic acetylcholine and muscarinic acetylcholine receptors
an example of two very different receptor subtypes
