Opioids Messge

Question 0

Address

Answer 0

Confirs selectivity for a particular subtype

Question 1

Message

Answer 1

Component of the ligand that defines primary receptor recognition (eg to a receptor family)

Question 2

NorBNI is essentially two

Answer 2

Naltrexones

Question 3

MesonorBMI

Answer 3

Is a mirror image, both the rings come OUT of the page

Inverted stereochemistry of address

Question 4

Left/right is the m or a

Answer 4

Left is the message, right is the address

Question 5

Nor BMI is … Selective

Answer 5

Mew and kappa antag

Question 6

Meso nor BMI is …

Answer 6

Selective kappa antagonist

Question 7

So the address is different by they are acting on the same receptor? Why ???

Answer 7

Basic nitrogens sit in the same place, you can strip away everything else and it still works

Question 8

Kappa pharmacophore consists …

Answer 8

Opioid message

Address: spacer+2nd basic nitrogen or other cation (interacts with glutamic acid in side chain)

Question 9

Delta pharmacophore

Answer 9

Opioid.message
Address: spacer and aromatic ring

(Found on NTI)

Question 10

Can the delta antagonist be converted into a kappa antagonist by making use of the kappa antagonist pharmacophore?

Answer 10

Yes. Use a guanadine after the aromatic ring. Has three basic atoms so covers a wide area

Question 11

Why do we have some scope with the basic group

Answer 11

The proton in the N that is shared with the acidic group in the receptor has to be in the right place, not the actual N molecule

Question 12

What potent kappa antagonist is produced from combining the delta and kappa addresses

Answer 12

GNTI (has the guanadine)

Question 13

Four main ways to alter the opioids

Answer 13

Change N-substituent for differing efficacies; (agonist – partial agonist – antagonist)
Change C3-substituent to change potency and pharmokinetic properties
Use of side chains (e.g. in orvinols) to change efficacy
Use message-address principle to access selective ligands

Question 14

Most ligands have had the phenylpiperidine motif with the phenyl ring in an …. configuration

Answer 14

Axial

Question 15

What happens if we have an equatorial ligand?

Answer 15

N protons still reach to interact in same places so you get efficacy
But you only get antagonists as the r groups extent to different area of space

Question 16

If the N-substituent in this new series of phenylpiperidines does not influence the efficacy of the ligands (they are all antagonists), then perhaps it could be used to …

Answer 16

influence potency and selectivity and pharmacokinetic properties
Why?major sideeffect is GI sideeffects such as constipation in a hospital setting. So if you could develop and antagonist that works in the perifery maybe you could combat this and administer with morphie

Question 17

How to stop something crossing the BBB

Answer 17

Make it highly charged like a zwitter ion

Question 18

What is being developed by Glaxo as a preventative agent for the GI problems associated with opioid pain relief after surgery

Answer 18

Alvimopa

At physiological pH become a zwitter ion so does not cross the BBB

Question 19

JDTic was developed by

Answer 19

Combinatorial chemistry of library of phenylpiperidine series

Question 20

JDTic acts how

Answer 20

highly potent a selective antagonist for kappa opioid receptors.

Question 21

JDTic is even more confusing becuase

Answer 21

It binds in reverse

The n of the receptor binds to the message