Receptors as drug targets

Question 1

receptors and chemical messengers

Answer 1

crucial to communication systems of body

Question 2

where are most receptors embedded?

Answer 2

within cell membrane

Question 3

receptor as natural messenger is known as what type of ligand?

Answer 3

endogenous ligand which binds to site exposed on outer cell surface, causing receptors to change its shape

Question 4

binds to site exposed on outer cell surface, causing receptors to change its shape,
what fit?

Answer 4

induced fit

Question 5

The CHANGE in shape triggers further events on membrane and inside cell

Answer 5

NO chemical reactions occurs between messenger and receptor

Question 6

too many chemical messengers released =

Answer 6

cell “overheat”

Question 7

too few chemical messengers released

Answer 7

cell become “sluggish”

Question 8

agonists

Answer 8

drugs that mimic the natural messenger and activate receptor

Question 9

antagonists

Answer 9

drugs that block receptor - still binds to receptor BUT DOES NOT activate it

natural messenger is blocked from activating it

Question 10

How to design agonist

Answer 10

1) drug - correct binding groups
2) correctly positioned groups
3) drug must be right size to FIT binding site

Question 11

what are the important binding groups??

Answer 11

consider:
VDW bonds
Ionic bonds
H-bonds

Question 12

can different compounds interact in the same way?

Answer 12

similar groups

Question 13

missing interactions means

Answer 13

POOR activity

Question 14

binding interactions cannot be TOO strong

Answer 14

neurotransmitter would not be able to leave and receptor cannot return to its original shape

Question 15

use positions of binding groups to explain difference in ______

Answer 15

activity

Question 16

enantiomers: mirror imagine, strong?

Answer 16

not strong as strong as original molecule as they are NOT the same shape

not interact with all of the binding region of receptor AT SAME TIME

Question 17

Pharmacophore

Answer 17

decides if drug will work as messenger or not
(do they contain the correct binding groups with the correct position)

Question 18

consider size and shape:
with an additional methyl group - Meta-methyl group

Answer 18

STERIC shield; prevents structure from sinking deep enough into binding site for effective binding

level of flexibility in the binding site

Question 19

how are agonists different in terms of structure to natural messenger?

Answer 19

Binding site: several a.a residues and peptide links - all of which might be capable of interacting with visiting molecule

Question 20

what are allosteric modulators?

Answer 20

indirect agonist effect.
mimic action of endogenous modulators and enhance action of natural or endogenous chemical messenger

(benzodiazepines used as sleep medicines target allosteric b.s. of the GABAA receptor)

Question 21

antagonists acting at the binding site

Answer 21

1) drug is right shape to bind to receptor b.s., but FAILS to change the shape of binding site or distorts in wrong way

2) find different binding regions within binding site not used by natural chemical messenger - binding of natural chemical messenger = induced fit (activates receptor)
binding of antagonists leading yo a different induced fit

Question 22

How to design antagonist? acting OUTSIDE binding site

Answer 22

1) allosteric modulators - ‘modulate’ activity of receptors by either enhancing or diminishing it

2) Umbrella effect - molecule act as shield/ umbrella (antagonist bind yo region of receptor) prevents Normal messenger from reaching b.s.

Question 23

Partial agonist definition

Answer 23

compound acts as an agonist and produces biological effect,
effect is not as great as FULL agonist

bind in TWO different ways - using different regions in binding site: one binding activates the receptor(agonist effect) / others not does (antag effect)

Question 24

conformational change induced

Answer 24

not ideal and subsequent effects of receptor activation are decreased

Question 25

what is a receptor subtype?

Answer 25

defined by the pharmacological characteristics of the site and is based on the availability of selective agonists and antagonists for the subtypes

Question 26

What is the receptor theory? see graph on PP

Answer 26

receptors does not have fixed inactive conformation
continue to change shape

equilibrium A) resting state <> agonist binding site
B) addition of agonist <> b.s. taken
C) addition of antagonist <> blocking
D) addition of INVERSE agonist <>
e) addition of partial agonist

equilibrium is shifted to active conformation but not to full extent as a FULL agonist (e - partial)

Question 27

affinity

Answer 27

of drug for receptor is a measure of how strongly that drug bind to receptor. aff constant (Ki)

Question 28

efficacy

Answer 28

measure of the max biological effect that drug can produce as a result of receptor binding

Question 29

does comp w high aff have high eff

Answer 29

not necessarily

Question 30

potency

Answer 30

refers to amount of drug require to achieve a defined biological effect - smaller the dose required = more potent
possible for drug to be potent (i.e. active in small doses) low efficacy

Question 31

how is aff, eff and potency measured?

Answer 31

dose-response curves; eff refers to max effect potency to dose req to achieve and effect

Question 32

potency is measure by ___% effective conc, EC_
(similary to IC_ in enzyme inb=inhibition); units of conc

Answer 32

50%
50
50