Medicines Design - Husbands

Question 1

What is the effect of stress on CREB?

Answer 1

CREB causes the release of dynrophin (a kappa agonist), which stimulates GABA production, which inhibits dopaminergic neurones

This can cause a lack of pleasure at doing certain things (anhedonia)

Question 2

Why is it often vital to test compounds in the correct animal model?

Answer 2

BU08028 in mice showed a full agonist response at mu and zero effects at NOP

In humans it showed the action at NOP and the partial agonism at mu that was expected

This was the same drug!!!

Question 3

What produces the pharmacological effects in opium?

Answer 3

The alkaloids

Question 4

What affect could acetylisation have on a drug?

Answer 4

Increase lipophilicity, and so BBB penetration

Could also reduce side effects

Question 5

What is the relationship between NOP and buprenorphine?

Answer 5

Buprenophine (a mu partial agonist) is also an agonist at NOP receptors which has a synergistic effect with mu, just without the side effects!

So a full analgesic effect can be recieved by just a partial agonist

Question 6

What is Laudanum?

Answer 6

An opioid in ethanol (alcohol)

Question 7

What are the 5 main things that will effect a drugs ability to get into the brain?

Answer 7

The number of H-bonding groups (donor and acceptor) –> Maximum of 1

Lipophillicity –> LogD (taken at pH of interest) = 1-3

Polar Surface Area (PSA) –> Total surface of polar atoms (eg, oxygen and nitrogen) = <90A with less than 6 N+O

Molecular Weight –> <400Da

Acidity –> No acids are best

Question 8

Which diastereoisomer of tertiary alcohols can give a greater analgesic potency when specific alkyl groups are added

Answer 8

The one with the R group in the middle

Question 9

What are the 3 basic ways of getting drugs into the brain?

Answer 9

Passive Diffusion –> Used mainly by lipophillic molecules

Active Transport –> Molecules that are needed like glucose and AAs are moved via transport proteins

Receptor-Mediated Transport (endocytosis) –> For drugs like insulin

Question 10

What are the 3 functional moieties that are needed for an NOP agonist

Answer 10

A) A heterocyclic moiety

B) A group containing a basic nitrogen

C) A lipophillic moiety attatched to the basic nitrogen

Question 11

What is common to all ‘morphine like’ drugs?

Answer 11

An axial aromatic ring

Question 12

What is Buproprion?

And why is its effects often only modest?

Answer 12

A dopamine and NA reuptake inhibitor with antidepressent effects

Often used in smoking sessation

It acts to simulate POMC neurones, which have anorexigenic effects –> Helping people lose weight

However this stimulation can lead to compensatory autoinhibitory feedback by endogenous opioids…causing limited weight loss

Question 13

What are the best groups to add to the following drug?

Answer 13

Question 14

Why is there a high interest in CB1 antagonists as anti-obesity drugs?

And what is Rimonabant’s main problem?

Answer 14

It is well known that cannabis will stimulate feeding, so logic states that by antagonising CB1 we will prevent feeding

The main problem is it is too lipophillic –> Analogues have been made to reduce this

Question 15

What are 2 key components of a drug that can access the brain?

Answer 15

An aromatic ring

A basic nitrogen

Question 16

Explain the effects of Nalorphine

Answer 16

Antagonist at Mu –> reversing the effect of morphine

Agonist at Kappa

Question 17

Answer 17

Decrease: MW and PSA –> Could remove large aromatic groups

Increase: The ClogP (lipophilicity) –> could be done by removing H-bonding groups

Question 18

In terms of CNS drugs, what is the significance of internal H-bonds?

Answer 18

They reduce the negative impact on CNS penetration

Question 19

What do we affect by changing specific groups?

Answer 19

Question 20

What is the main active metabolite of heroin?

And how is it made?

Answer 20

6-monoacetylmorphine

Via hydrolysis with water

Question 21

What’s a benzomorphan?

Answer 21

A simplified opioid, made by removing several aromatic groups

It’s activity is pretty much the same as morphine despite the changes

Question 22

What is an Enkephalin?

And what is their main problem?

Answer 22

Endogenous opioids

Tyrosine (in all enkephalins) is highly flexible (amine group), meaning that D-Tyr will bind whilst L-Tyr may not

Question 23

When replacing the nitrogen methyl group in opioids, at what carbon length is the maximum anaglesic effect achieved?

Answer 23

6 carbons

Question 24

What is Alvimopan?

Answer 24

A preventative agent of opioid caused GI problems

The nitrogen is protonated at physiological pH, so wont cross the BBB….meaning it only works in the periphery, which is perfect!!

Question 25

What is Buprenorphine?

Answer 25

A partial mu opioid agonist and full kappa antagonist

Question 26

What is the base molecule that etorphine is based on?

Codeine or Morphine?

Answer 26

Morphine (3-OH not MeO)

Question 27

What is the most active form of methadone?

Answer 27

L-(R)-Methadone

Sold as a racemic mixture (D-isomer has NMDA antagonist activity)

Question 28

Why does methadone only need to be taken once daily?

Answer 28

More lipophillic than drugs like morphine, so it is more widly distributed, meaning it has a greater duration of action

Question 29

What does increasing LogD do?

Answer 29

Increases the lipophillicity, which means a greater BBB penetration (up to a point)

Question 30

Why could mu opioid receptor antagonists/inverse agonists be useful in treating obesity?

Answer 30

As mu receptors are used in the reward pathway when eating, so by having inverse agonists or antagonists at mu we could reverse the effect

Question 31

What is the address molecule for delta and kappa opioid antagonists?

Answer 31

Delta –> 2nd aromatic ring

Kappa –> Spacer then 2nd basic nitrogen (or other small cation)