Term
| Most drugs have a molecular weight between what and what g/mol? |
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Definition
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Term
| How does MW and selectivity relate? |
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Definition
The higher the molecular weight, the MORE selective it is
IE - smaller compounds and ions do not selectively bind to receptors |
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Term
| Normally, ____ isomer is active pharmacologically. |
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Definition
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Term
| The higher the KD the ______er the affinity between drug & receptor. |
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Definition
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Term
| a drug with a KD of 1nM has a much _____er affinity than a drug with a KD of 1 mM for receptor X |
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Definition
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Term
| What types of interactions mediate how drugs are INITIALLY attracted to their receptors? What about when the the drug is at the receptor and being pulled in to the binding pocket of the receptor? |
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Definition
Initially - ionic
Near binding pocket - hydrogen and van der Waals bonds |
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Term
| What is the exact definition of KD? |
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Definition
| Concentration of drug required to bind HALF of the receptors |
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Term
| Broadly, what is the general range of KD's? |
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Definition
| mM (10 ^-3) to about pM (10^-12) |
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Term
| When binding specificty is not perfect, what is the result? |
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Definition
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Term
| What is the equation of the law of mass action? |
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Definition
| L (ligand) + R (inactive receptor) -->/<-- LR* (active receptor) --> Biological response |
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Term
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Definition
| Reactants ( [L] & [R]) divided by Products ( [LR*] ) |
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Term
| How is efficacy different from affinity? |
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Definition
Affinity - strength of interaction between ligand and receptor
Efficacy - the strength of the biological effect |
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Term
| What is the definition of an agonist? |
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Definition
| Substance that binds a receptor and produces a biological response |
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Term
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Definition
Substance that can generate the MAXIMUM biological response by activating 100% or even less of the receptors
Efficacy = 1! |
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Term
| What is a partial agonist? |
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Definition
A substance that can fully cause a maximum biological response even when bound to 100% of the receptors
0 |
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Term
| What is an inverse agonist? |
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Definition
| A substance that produces a decrease to 0 from the basal activity of a system (a system always has some activity - this these will decrease it to 0) |
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Term
| What is an allosteric agonist or enhancer? |
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Definition
| chemical compound that INCREASES THE AFFINITY/EFFICACY OF OTHER AGONISTS by binding/altering ANOTHER site of a receptor (so NOT the site the agonist binds) |
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Term
| What type of antagonism is chealtion an example of and why? |
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Definition
| Chemical antagonism - direct chemical interaction between agonist and antagonist, rendering the agonist pharmacologically inactive |
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Term
| What type of antagonism is ACh and Epi an example of and why? |
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Definition
| Physiological antagonism - interaction of 2 different agonists that act independently (at diff. receptor sites) of eachother and cause OPPOSITE effects |
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Term
| What is indirect antagonism? |
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Definition
| When a biological response is inhibited by acting at a site beyond (downstream) of the recepor - agonist binding |
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Term
| What is the most frequently seen antagonist in clinical practice? |
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Definition
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Term
| Competitive antagonists have affinity but no _____. |
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Definition
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Term
| What are the different types of competitive antagonists? |
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Definition
Equilibrium (reversible) - can be OVERCOME by increasing agonist at receptor site
Non-equilibrium (irreversible) - increaseing antagonist increases antagonism, but increasing agonist CANNOT overcome antagonism |
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Term
| What is an allosteric antagonist? |
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Definition
| reduces affinity of agonist by binding receptor AT DIFFERENT SITE which changes the conformation of the receptor which changes the receptor agonist affinity/efficacy |
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Term
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Definition
| The dose of drug required to produce 1/2 (50%) OF ITS OWN maximum response |
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Term
| What is the difference between a graded response and a quantal response? |
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Definition
Graded - X-axis is drug dose and Y-axis is biological response IN ONE INDIVIDUAL
Quantal - X-axis is still dose but Y-axis is percent of patients that answered Yes to efficacy (Yes, with 100 mg my headache went away) |
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Term
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Definition
| comparision of ED50 values of 2 drugs that MUST WORK BY SIMILAR MECHANISMS |
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Term
| Drug A has a smaller ED50 than drug B. Which drug has a higher potency? |
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Definition
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Term
| What is the relationshop between potency and affinity? KD vs ED50? |
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Definition
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Term
| The more potent drug is always better than the less potent one? |
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Definition
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Term
| What is the difference between intrinsic activity and efficacy? |
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Definition
| Small diff., therefore they are used interchangably...intrinsic activity takes into account spare receptors |
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Term
| What are the changes to an equilibrium competitor antagonist to an agonist curve look like? |
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Definition
| RIGHT SHIFTED - Potency decreases but EFFICACY remains the SAME |
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Term
| For a irreversible antagonist / agonist graph, what are the changes seen once antagonist is added? |
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Definition
EFFICACY decreases
Potency decreases a little bit - there is a slight rightward shift, but not as much as reversible antagonism |
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Term
| What other graph of antagonism looks very close to irreversible antagonism? |
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Definition
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Term
| A partial agonist (in the presence of a full agonist) appears to be a _____. Describe. |
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Definition
| antagonist....its not really but since its efficacy is less than 1, when it is averaged out with something whose efficacy is 1 (full agonist), it will bring the "average efficacy" down |
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Term
| Name 2 people that helped discover receptors. |
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Definition
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Term
| Most receptors weight between what and what kilodaltons. |
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Definition
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Term
| What are the groupings of receptors and an example |
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Definition
Super families (G protein coupled)
Families (Adrenergic receptors)
Subypes (alpha1 adrenergic) |
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Term
| What are the chacteristics of 7TMSGPCR |
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Definition
7 transmembrane nonpolar loops
3 extra cellular loops
3 intracellular loops
Amino end outside cell
Carbonyl end inside cell
Heterotrimeric G-proteins bind to THIRD INTRACELLULAR LOOP + Carboxy terminal end |
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Term
| What is the TIME FRAME of 7TMS GCPR? |
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Definition
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Term
| What are 4 endogenous activators of 7TMS GCPR? What are their actual receptors? |
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Definition
Norepinephrine - alpha & beta receptors
Serotonin - 5-HT receptors
ACh - M1-M5 receptors
Histamine - H1 and H2 |
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Term
| What are the three G-alpha subunits we need to know and what is their intracellular consequence one active (released from G-gamma/G-beta |
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Definition
alpha-S: increase cAMP
alpha-I: decrease cAMP
alpha-q/11: increase Ca, IP3 and PKC |
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Term
| Gs: how does it increase cAMP? |
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Definition
| Activates AC. AC turns ATP into cAMP |
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Term
| Gi: how does it decrease cAMP? What else can it do? |
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Definition
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Term
| What does the beta-gamma G subunit do in cardiac cells? |
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Definition
| When M2 is bound by ACh, beta-gamma will open K+ channels (hyperpolarization, decreased HR) |
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Term
| How does Gq/11 do its action? |
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Definition
| Its alpha subunit activates PLC which cleaves IP3 off of PIP2. IP3 opens sarcoplasmic Ca channels and activates PKC (i think.... or PLC might do this) |
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Term
| Once GPCRs are activated, what happens to them? |
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Definition
| They are phosphorylated by GPCR kinase on either a serine residue of the 3rd intracellular loop or at the receptor site. THis phosphorylation attracts beta-arrestin. beta-arrestin internalizes the GCPR and blocks reformation of G heterotrimer and GPCR. After internalization, it can either be degraded in a lysosome (if it was stimulated long-term) or recycled and put back on membrane (if only stimulated short term) |
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Term
| What is the difference between desensitization/tachyphylaxis and downregulation/tolerance? |
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Definition
Desensitization is due to the INTERNALIZATION of the receptor from when drugs are used repeatedly at the same dose
Down-regulation is also a decrease in the response, but its due to the DEGREDATION of the receptor from a CHRONIC LONG-TERM expose to agonist |
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Term
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Definition
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Term
| When do receptor levels increase (which is what happens in sensitization? |
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Definition
from long-term presence of antagonist
OR
absence of endogenous neurotransmitters |
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Term
| Name 2 examples of Ligand-gated channels (ionotrophic receptors) |
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Definition
| Nicotinic acetylcholine receptor, and GABA |
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Term
| What is the purpose of an ionotropic receptor? |
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Definition
| change cell membrane potential upon activation |
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Term
| Tyrosine kinase receptors have a _____cellular _____-binding domain |
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Definition
| extracellular hormone-9binding domain |
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Term
| What are tyrosine kinase receptors usually involved in? Name 4 of their activators? |
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Definition
Cellular growth and differentiation
Cellular function
EX - insulin, EGF-epidermal growth factor, PDGF-platelet derived growth factor, and ANF - atrial natriuretic facotr |
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Term
| What is the time frame for ionotropic receptors VS. tyrosine kinase receptors? |
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Definition
ionotropic - miliseconds
tyrosine kinase - minutes/hours/days |
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Term
| What is unique about the tyrosine kinase activation pathway? |
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Definition
| When ligands bind, the receptor subunits will cross-phosphorylate eachother, allowing them to get activated longer |
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Term
| When cytokine receptors get activated, what happens next? |
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Definition
| JAK (Janus kinase) phosphorylates them. Phosphorylated receptors now attract STAT. JAK then Pi's STAT and 2 STATs dimerize and enter the nucleus for tx |
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Term
| What is the end result of cytokine receptor activation? |
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Definition
| tx regulation of inflammtory mediators and hematopietic facotrs |
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Term
| What is the time frame of operation for cytokine receptors? |
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Definition
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Term
| Name 3 endogenous activators of cytokine receptors? |
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Definition
| Growth hormone, erythropoietin, interferon |
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Term
| What are the 3 functional domains of intracellular receptors? |
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Definition
| Hormone binding domain, DNA binding domiain, tx activating domain |
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Term
| What is the activity of intracellular receptors related to? Time frame? |
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Definition
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Term
| What are some endogenous activators of intracellular receptors? |
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Definition
| Glucocorticoids, mineralcorticoids, sex steroids, Vit D, thyroid hormone |
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