17. GCPRs as Drug Targets

Question 1

How common are GCPRs used as drug targets?

Answer 1

40% of drugs target GCPRs

Question 2

What are GCPRs used for?

Answer 2

• mood and behavior
• immune system function
• vision and smell
• autonomic nervous systme regulation

Question 3

What is the GCPR drug target target that we are going to be focused on?

Answer 3

Seratonin receptors

Question 4

Explain the difference between the allosteric site versus the othosteric site.

Answer 4

orthosteric site - the site where the endogenous ligand binds
allosteric site - other regions that still have important effect when ligand binds

Question 5

How does orthosteric agonism work?

Answer 5

The drug binds in the orthosteric site.
(agonist or antagonist)

Question 6

Explain allosteric modulators (positive, negative, and neutral).

Answer 6

binds to the allosteric site –> changes structure of GCPR –> alters affinity of GCPR for its ligand (increase, decrease, or keep neutral)

Question 7

Explain how GCPRs are recycled (w/ GRK)

Answer 7

• ligand binds to GCPR
• G-protein receptor kinase (GRK) that phosphorylates the c-terminal tail of the GCPR
• when the c-terminal is phosphorylated beta arrestin can bind
• beta arrestin can trigger endocytosis –> endocytosed in endosome
• receptor can be recycled to the surface

Question 8

How are GCPRs degraded?

Answer 8

• ligand binds to GCPR
• GRK phosphorylates the c-terminal of GCPR
• after phosphorylation –> beta arrestin can associate with the c-terminal
• gets endocytosed by endosome
• gets degraded by lysosome

Question 9

If you could inhibit a specific GCPR from binding beta arrestin, what would happen?

Answer 9

The receptor would have a longer half-life and last longer overall.

Question 10

What happens when Wnt isn’t bound to frizzled?

Answer 10

• Wnt can be sequestered by other components extracellularly
• GSK constantly phosphorylates beta-catenin
• beta-catenin is ubiquinated –> degraded by proteasome

Question 11

What happens when Wnt is bound to frizzled?

Answer 11

• sequesters GSK (prevents beta-catenin phosphorylation/ubiquination/degradation)
• beta-catenin can go into the nucleus and activate transcription of target genes

Question 12

Explain Risperdal’s MOA.

Answer 12

• binds tightly to dopamine D1 and D2 receptors as antagonists
• target: serotonin receptor, HDAC inhibitor, dopamine (complex - nonselective)

Question 13

Describe Claritin and its MOA.

Answer 13

Target: histamine H1 receptor
* inverse agonist

Question 14

Explain the role of histamine in allergic reaction and inflammation.

Answer 14

• An antigen can penetrate the epithelium and encounter a mast cell.
• Allergens can trigger mast cells to release histamines
• Histamines cause other cells to secrete mucus, sneeze, etc.

Claritin: If you can block/inhibit histamine signaling, you can prevent the cells from responding to histamine (insensitive to histamine - can’t detect it)

Question 15

Explain Salmeterol and its MOA.

Answer 15

• Used for asthma and COPD treatment
• target: beta-adrenoceptor
• agonist
• used in conjunction with albuterol
  (albuterol - short term; salmeterol - long term)

Question 16

Explain the MOA of fentanyl.

Answer 16

• target: u-opioid receptor (GCPR)
• receptor agonist
• Ca2+ is involved with releasing neurotransmitters into the synapse
• when a opioid binds the receptor on presynaptic neuron –> decrease of Ca2+ in the presynaptic neuron
• decrease of Ca2+ in the neuron –> decrease release of excitatory neurotransmitters into the synapse (glutamate)
• activation of the opioid receptor on the postsynaptic neuron –> increases K+ leaving the neuron (efflux)
• increased K+ efflux –> decreases response of postsynaptic neuron = inhibits neuron activity