Wk4 Drug Agonists And Antagonists Of Pharmacology

Question 1

What is the first problem of receptor signalling

Answer 1

The problem is to form some picture of cell structure that will explain the fact that a few thousand of these molecules when they unite with the cell suffice to modify its functions.

Question 2

Ways of regulating cell function

Answer 2

altered membrane potential
altered enzyme activity
altered gene expression
Most drugs affect cell function via (physiological) receptors

They act “hormone‐like” = an artificially made hormone molecule may directly be used as a drug
e.g. glucocorticosteroids or tyroxine

Question 3

Receptors and the effects of drugs

Answer 3

How drugs produce effects by binding to receptors
‐ various ways in which effects are produced ‐ agonism How drugs block effects by binding to receptors
‐ ways in which effects blocked or reduced –
antagonism and desensitization

Question 4

Allosteric effects on receptors

Answer 4

The GABAA receptor
(gamma‐amino‐butyric acid)
• ligand‐gated chloride ion channel in the brain
• benzodiazepine agonists bind to GABAARs
and increase the affinity of the GABA binding site for GABA, thereby increasing channel opening

Question 5

Benzodiazepine receptor ligands

Answer 5

Agonists – diazepam, lorazepam
Antagonists – flumazenil (“antidote”)
Inverse agonists – beta‐carbolines

Question 6

Glutamate-gated chloride receptors

Answer 6

common channels in the nervous system

important target for anti‐parasitic drugs e.g. ivermectin

Question 7

“Spare receptors”

Answer 7

Some highly efficacious agonists (super‐agonists) can produce a maximal
response from the cell without binding to all of the available receptors

For example, goserelin (Zoladex) is a super‐agonist of the gonadotropin‐releasing hormone receptor (GnRH‐R). It suppresses production of the sex hormones (testosterone and estrogen), particularly in the treatment of breast and prostate cancer.

Question 8

Partial agonists

Answer 8

Low efficacy, partial agonists cannot produce the cell’s maximal response, even when they have bound to all of the available receptors.

1 example for partial agonists at particular receptors: buprenorphine is an opioid used to treat opioid addiction, moderate acute pain and moderate chronic pain

Question 9

Competitive antagonists

Answer 9

atropine (from the deadly nightshade) at muscarinic receptors propranolol at beta‐adrenoreceptors
sildenafil at phospho‐diesterase 5 (PDE5) competing with cGMP
• bind reversibly, at the same site as the (natural) agonist
• produce parallel shift to the right of agonist dose/response curves

Question 10

Irreversible antagonists

Answer 10

phenoxybenzamine at alpha‐adrenoreceptors
second/third generation proteasome inhibitors (based on bortezomib)

– bind irreversibly, at the same site as the agonist, forming a covalent bond or binding incredibly tight

– decrease the maximal response to agonists
•may produce an initial shift to the right of the dose/response curve with no decrease in max
•evidence for spare receptors

Question 11

Types of antagonism

Answer 11

Competitive antagonists

Irreversible antagonists

Allosteric antagonists

Channel blockers

“Physiological antagonists”

Question 12

Allosteric antagonists (rare)

Answer 12

gallamine at the muscarinic receptor beta‐carbolines at the GABAA receptor —> allosteric (enzyme) inhibition
‐ bind (reversibly) at a distinct site from the agonist and decrease agonist affinity
‐ reduce likelihood of agonist binding

Question 13

Channel blockers

Answer 13

phencyclidine at the NMDA receptor
–bind inside the channel (“plug”) and prevent the passage of ions
–binding of channel blockers tends to be enhanced by receptor activation
•use dependence

Question 14

Physiological antagonists

Answer 14

They antagonise the physiological effect of some agonists, but via different mechanism

1) several substances that have anti‐histaminergic action despite not being ligands for the histamine receptor: epinephrine and other such substances are physiological antagonists to histamine
2) endocrine disruptors; some of the inhibit conjugation reactions

Question 15

Desensitization

Answer 15

Prolonged or repeated exposure to an agonist reduces the response to that drug

Tolerance to heroin
‐ increased adenylyl cyclase activity in the brain

Inactivation of nicotinic receptors
‐ receptor driven into an inactivated state

This may come by through up‐regulation of the receptor for the respective drug… among other mechanisms.

alcohol dehydrogenase is upregulated so if you have often exposure to alcohol your liver will grow with the challenge

Question 16

Receptor classification

Answer 16

Receptors are classified on the basis of the selective action of drugs
They are named according to the transmitter or hormone with which they interact – e.g. acetylcholine receptors
Most hormones interact with more than one type of receptor
– (subtle) differences in protein structure underlie differences between subtypes

Question 17

Experimental proof that transmitters may act on more than one receptor

Answer 17

This is experimental proof of two different classes of acetylcholine (ACh) receptors: “muscarinic” and “nicotinic” ones.
Only after the high‐affinity muscarinic ones have been poisoned, the low‐affinity nicotinic ACh receptors become visible.

Question 18

Receptor super-families

Answer 18

Integral ion channels eg nicotinic receptor glycine receptor

Integral tyrosine kinases eg insulin receptor

Steroid receptors = nuclear receptors e.g. estrogen receptor, androgen receptor

G protein coupled receptors eg muscarinic rec. adrenoreceptors

Cytokine receptors e.g. prolactin receptor, EPO receptor growth hormone
TNF receptor

Question 19

Some more words on nuclear receptors

Answer 19

DBD = DNA‐binding domain 
LBD = ligand‐binding domain 
RE = response element

Question 20

Nuclear receptors

Answer 20

• ACT in the nucleus, but are most often - located in the cytoplasm
  Their ligand-binding domain functions like a folding sensor - without steroid ligand, it is unfolded
• with steroid it gets folded.
  The DNA-binding domain mediates binding of nuclear receptors to thousands of sites within the genome.