Week 3 - Medicinal Chemistry: Selective Serotonin Reuptake Inhibitors

Question 1

Background INFO of drug developement

Answer 1

• Drug discovery for drugs that target CNS is challengning due to issue of getting drug across the BBB
• Required to use animal models to test efficacy + work out safety margins (between efficacy + toxicity) for the drug before testing on humans in clinical trials
• New drug development is expensive >1 billion (paid for by private companies ~ regain money as drug has patent rights)
• PROBLEM: evidence base publication of clicnial trials can be classes as positive, neagtive or neutral depending on reseracher
  - but when examined by FDA they make the final decison and some trials arent as effective as claimed to be

Question 2

What are the challenges specifc to developing CNS drugs

Answer 2

• CNS is poorly understood and humans are complex = makes process harder to develop new drugs
• Hard to get drugs across the BBB
  - when developing drugs try to remove N-H and O-H groups
• Pre-clinical safety and efficacy testing is required BEFORE able to obtain license for clinical trials = long process
  - in USA need a FDA
• Requries animal model / animal testing to establish safety + effective dose
  
  • HARD to create animal models for human CNS conditions
  • we don’t know how non-human CNS issues like depression look like

Question 3

Explain the Drug Discovery Process

Answer 3

PRECLINICAL:
(during this stage the molecule shape may be changed by chemists testing it)
1. Target identification
2. Hit identification
3. Hit-to-Lead
4. Lead optimisation
- most expensive step as don’t get money back until marketing authorisation = could potentially lose all money invested
5. Preclinical development

CLINICAL:
(during this stage molecule shape remains same + chemist must produce enough of drug to undergo trials)
1. Clinical trials (Phases I to III)
- MOST important step

POST-MARKETING:
(during this stage molecule shape remains same)
1. Marketing authorisation

Question 4

What are the 2 classess of antidepressants

What 2 ways can antidepressants be classed

Answer 4

1. Mode of action (MoA)
   - e.g. SSRIs, SNRIs, MAOIs
   - SSRIs are most prescribed antidepressants
2. Chemical structure
   • e.g. tricyclic, tetracyclic

Question 5

What is a common feature amongst compounds that target CNS

Answer 5

1. Basic amine (NR group e.g. NH2)
2. Many aromatic rings
   - hydrophobic
3. Few polar groups (S ~ sulphur atom)
   - not a lot of polarity
4. Mostly hydrophobic / lipophillic
   - contained Cl group
5. Is constricted
6. Presence of methyl or ethyl group (instead of H)
   - blocked serotonin activity in sertraline development

Question 5

How was Sertraline Discovered

SSRIs

Answer 5

1. Similairites between a known neuroleptic compound was found in 1973
   
   • compound reduces nerve activity
2. Made some compounds and tested their ability to prevent 5HT3 (serotonin), dopamine and norepinepherine (noradrenaline) reuptake in rat brains

PROCESS:
1. Get rat brain, homeogensie it, centrifuge it and collect solid matter
2. Suspend solid matter in solution containing radioactive serotonin + allow to sit for 10 minutes
3. Add compound (prevents reuptake)
4. Collect solid (cells) via filtration
5. Measure radioactivity (check cells if taken up serotonin) if YES = ineffective compound / drug
6. Change conc. of drug compound + measure if radioactive uptake changed
7. SERTRALINE was then discoverd (by Pfizer)
- became a generic medicine when patent expred in June 2006

IC50 = half of the maximal inhibitory concentration (IC)
- measures drug efficacy
- selective serotinin inhibition = low IC50 fo 5HT

Question 6

Discovery Process of Fluoxetine (prozac)

SSRI Antidepressant

Answer 6

More a.depressants were developed by adding diff. functional groups (in diff. places around the ring) to already exisiting molecules

1. First seen in 1970s
2. Phase 1 started in 1976
3. Phase 3 started in 1981
4. Went into clinics in 1983
5. Was approved in 1987
   - a total of 16 years

Question 6

Animal Testing

Serotonin Development

Answer 6

Animal testing has NO / LITTLE link to human conditions
- used ONLY to estab;ish efficacy, safety margins, toxcity, dosing etc.

PROCESS:
- Give small dose of serotonin to rat
- has to be small dose to prevent effects of serotonin from showing at start of test (i.e. tremor, head twich etc.)
- Then give rate SSRI AND observe to see if effects occur
- if occur = DRUG effective (in preventing reuptake of sertonin)

AIM: is to measure the effects of drug dose compound on the conc. of specific compounds (e.g. 5HT, NA)

Animal testing just relates to serotnin in brain DOES NOT have relations to the condition (depression in humans)