Intro to Receptor Theory

Question 1

define a drug receptor

Answer 1

a cellular macromolecule, or an assembly of macromolecules, that is concerned directly and specifically in chemical signaling between and within cells; the combination of a hormone, neurotransmitter, drug, or intracellular messenger with its receptor(s) leads to a change in cell function

Question 2

describe the recognition site of a drug receptor; list the 2 types of modulation that occur here via drugs

Answer 2

the site is the region of the receptor macromolecule to which ligands bind; can have either
orthosteric modulation: where the drug binds to the same location as the natural ligand or
allosteric modulation: where the drug binds at another location and causes a conformational change in the receptor

Question 3

describe agonists

Answer 3

increase the activity of a receptor; include some drugs and MOST natural ligands; have affinity AND efficacy

Question 4

describe antagonists

Answer 4

bind to receptors but DO NOT trigger generation of a signal; most drugs are antagonists that interfere with the ability of an agonist to activate a receptor; ONLY have affinity

Question 5

list the 4 different types of receptors; give an example of each

Answer 5

1. ion channel-linked receptor: sodium and calcium ion channels
2. G protein-coupled receptors: muscarinic receptors
3. enzyme-linked receptors: insulin and growth factor receptors
4. intracellular receptors: steroid hormone receptors

Question 6

define ion channel receptors

Answer 6

very fast! ligand binds receptor, which changes from a closed to an open state, allowing the channel to open and the magic to happen

Question 7

define G protein-couple receptors (GPCRs)

Answer 7

hella complex (seven transmembrane receptors) that induce many downstream biologic reactions and activate second messengers

Question 8

define enzyme-linked receptors

Answer 8

activate proteins!! ligand binds receptor leading to activation of proteins and therefore a cellular response

Question 9

define intracellular receptors

Answer 9

the slowest of all the receptors! ligand binds to a cytosolic receptor inside the cell, is transported to the nucleus, and binds to a DNA binding domain that interacts with a transcription activating domain that regulates genome expression (this process takes hours)

Question 10

define drug affinity, Bmax, and Kd

Answer 10

drug affinity: how strongly a drug/ligand binds its receptor; the strength of the attraction between the two

Bmax: the total concentration of receptor sites; more free drug leads to more binding until you reach Bmax and then all receptors are saturated

Kd: Bmax/2; is the equilibrium dissociation constant; if Kd is low then the binding affinity is high

Question 11

define drug potency/EC50/IC50 and efficacy/Emax

Answer 11

drug potency: the activity of the drug in terms of the concentration required to produce a define effect; depends on BOTH the affinity of the drug for its receptor AND the efficacy of the drug-receptor interaction

EC50: stimulatory potency
IC50: inhibitory potency

efficacy: the maximum biological effect a drug can produce by binding to a receptor;NOT THE SAME AS POTENCY

E50: Emax/2

Question 12

why is EC50 generally less than Kd?

Answer 12

it is not usually necessary to saturate half of the receptor to obtain half of the Emax; there are spare receptors just in case but not all receptors must be saturated for full effect

Question 13

describe full, partial, and inverse agonists

Answer 13

full agonists: can produce Emax under certain conditions

partial agonists: cannot produce maximum effect

inverse agonists: can be full and partial, but all decrease the baseline activity of the receptor

Question 14

compare and contrast competitive versus non-competitive/irreversible antagonists

Answer 14

competitive antagonists: compete for the same binding sites as the natural ligand, resulting in the same efficacy but a shift in potency, meaning you need more of the agonist to get the same effect around the competitive antagonist

noncompetitive/irreversible antagonists: change the activity of the receptor, resulting in the same potency but a shift in efficacy, meaning you can put all the drug you want in the system but you will never achieve the maximum effect because the antagonist changed the receptor for the agonist

Question 15

describe the conceptual framework of clark’s model

Answer 15

Clark says that drug response is a linear function of drug occupancy of receptor sites, meaning that a 25% occupancy would yield a 25% response, or Kd= [R][A]/[RA]

Question 16

describe the conceptual framework of arien’s model

Answer 16

Arien observed that different agonists apparently acting on the same receptor systems evoke different Emax in the same tissue, creating full and partial agonism concepts, so he introduced the concept of intrinsic activity (alpha) as a proportionality term between effect and fractional occupancy to scale the effect, meaning that 25% occupancy does not always equal 25% response, but that it now depends on the intrinsic activity, or the effectiveness of the drug-receptor complex in producing a response