Lecture 3: Response, Potency and Efficacy Flashcards
Agonist
-bind to receptor site
-enhanced cellular activity
-induced fit that activates receptor
Antagonist
-binds to and blocks receptor site
-blocks natural chemical from binding to receptor
-induced fit that does NOT activate receptor
Potency
-dose of drug required to produce particular effect of given intensity
-comparison based on doses that produce SAME effect (usually ED50)
-may be overrated
High potency
entire curve shifted left towards lower x values
low potency
entire curve shifted right to higher x values
Efficacy
-response resulting from DR interaction
-limited by toxicity
-more important than potency
Strong agonist
high affinity and high efficacy
Higher efficacy
curve reaches closer to 100%
-higher y value
lower efficacy
lower y value
Partial Agonist
-produce reduced response even at full occupancy
-cannot produce same maximal effect as full agonist
-may competitively inhibit response to full agonist
-related to drug binding. to inactive form of receptor
Partial agonist examples
-aripiprazole, D2
-buprenorphine, mu opiate
-buspirone, 5-HT1A
partial agonist structural basis
resembles a shape between agonist and antagonist
Partial Agonist theory
Level of response
full agonist > partial agonist > inactive compound > inverse agonist
Heroin Methadone example
-Buprehorphine (partial agonist) binds all receptors and provides about half effect of heroin as treatment for opiod addiction = nowhere for heroin to bind so no withdrawal
-Naloxone (antagonist) blocks all receptors but with no effect = no euphoria = withdrawal
Full agonist structure
-fits neatly
-loop c closes in
Partial agonist structure
-a bit bigger, sticks out
-loop c can close but not all the way
Antagonist structure
-bigger, sticks out of receptor
-loop c cannot close
Inactive to active form
Lecture 4 recording
As partial agonist concentration increases
more occupancy of receptors
-undos full agonist binding?? idk
as full agonist concentration increases
less occupancy of receptors
Increase partial concentration
decrease overall response
Assumption: adding enough partial agonist or antagonist
displaces full agonist
Inverse agonist
-requires constitutive activity (otherwise it’s just an antagonist)
-opposite response of agonist
-inactivates receptor?
-full or partial
-response can be altered by agonist, partial agonist, antagonist (shared binding site)
-stabilize inactive form of receptor
-ex: rimonobant (acomplia)-CB1 receptors
Inactive receptor + agonist
conformational change of receptor and interaction with G proteins
active conformation of receptor w/o agonist + inverse agonist
inactive receptor
no interaction with G proteins
Rimonobant (acomplia)
-inverse agonist
-binds to cannaboid (CB1)receptors
-reduced hunger, increased anxiety
-oops she never made it to the market
activation of CB1 receptors
-THC bind
-decreased anxiety, hunger, relaxation
constitutive activity
REQUIRED for inverse agonists
-active form of receptor
constitutive activity absent
same as antagonist
constitutive activity present
-inverse agonist lower than antagonist curve
-backward s curve
Endogenous agonist present
silent antagonist has backward s curve
endogenous agonist. absent
silent antagonist straight line
constitiutive absent, endogenous agonist absent
no effect from either
-straight horizontal line on top
constitutive activity, NO endogenous agonist
-silent antagonist no effect
-inverse agonist has effect
NO constitutive activity, endogenous agonist present
-both have same effect
Constitutive activity and endogenous agonist present
-both have effect
-inverse agonist has better effect
Receptor Antagonism
-DR interaction that interfres with or prevents the development of drug response by agonist
-competitive, noncompetitive, irreversible
Competitive Antagonism
-competing for active site
-reversible by increasing dose
-increase concentration shifts curve right
Log dose-response curve of AGONIST in presence of competitive antagonist
-shifts right
-reduction in effective potency of agonist
-need more agonist
Schild plot
-ability to calculate KD of ligand to generate P2 value
Binding affinity generally correlates with
the potency of antagonists
