GPCR and migraine

Question 1

Define migraine

Answer 1

Chronic migraine - 15 days or more per month are headache days

Question 2

Describe CGRPs role in migraine

Answer 2

Neuropeptide - abundant sensory neurons
Modulates neuronal activity
Drug discovery goal - develop CGRP receptor antagonist

Question 3

Describe CGRP

Answer 3

Large peptide
- Small molecule antagonist could not be designed
- Need to use high throughput screening to identify candidate molecules

Question 4

Describe screening

Answer 4

Requires a source of receptors - commonly manipulated to artificially express human receptor at higher levels - increases chances of finding initial hit

Question 5

Describe the SK-N-MC screening model

Answer 5

Lost receptors over time in continuous culture - makes identifying more challenging

Question 6

Describe the CGRP receptor

Answer 6

GPCR - Calcitonin receptor-like receptor and an accessory protein
Couldn’t use well-established medicinal chemistry
Opportunity for novel chemical space (new intellectual property)

Question 7

What is target engagement

Answer 7

Ability of a drug to bind its target

Question 8

Describe drug efficacy

Answer 8

Ability of a drug to have its desired effect

Question 9

Describe skin blood flow engagement model

Answer 9

CGRP is a vasodilator
Measures blood flow across species - used to quantify functional effects of receptor antagonism and establish target engagement

Question 10

Describe Telcagepant and Olcegepant

Answer 10

Challenges - Variable oral bioavailability, low in primate (high rate of first pass metabolism)
High doses needed to achieve acceptable blood conc.
Opportunity - good enough to proceed to human studies
(not pursued due to IV dosing - Olcegepant)

Question 11

Describe the possible use of monoclonal antibodies

Answer 11

Advantages - mAb so no liver toxicity associated with sml. molecules - long lasting/slow clearance - good as preventative
Challenges - expensive - difficult to administer - slow clearance