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Drug Disco > Opioids > Flashcards

Opioids Flashcards

0
Q

Structaral difference between morphine and heroin?

A

Two acetylation of two hydroxyl groups

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1
Q

Morhpine - how many chirals and what way?

A

5R, 6S, 9R, 13S, 14R

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2
Q

All other things being equal what makes something abusable

A

Faster access to the brain - greater rush

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3
Q

Heroin or morphine access the brain more quickly?

A

Heroin - more lipophilic (h donating groups have become esters) - crosses the BBB more easily

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4
Q

Which is more potent as an analgesic, heroin or morphine?

A

Heroin is 2x as potent as an analgesic

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5
Q

Which binds to opioid receptors with greater efficacy, heroin or morhpine?

A

Morphine.

Heroin has low affinity.

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6
Q

Heroin metabolites…

A

Heroin - 6-acetylmorphine - morphine - morphine 3-monoglucuronide

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7
Q

6-acetylmorphine potency and binding affinity

A

4x more potent than morphine with similar binding affinity

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8
Q

6-acetylmorphine has the acetyl on the left or right

A

Right

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9
Q

Define PD and PK

A

Pharmacokinetics is the study of the bodily absorption, distribution, metabolism, and excretion of drugs.
Pharmacodynamics is the study of the biochemical and physiological effects of drugs and the mechanisms of drug action.

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10
Q

structural difference between heroin and codeine

A

Codiene has a OMe on 3 instead of OH

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11
Q

Codeine potnetcy in relation to morhpine

A

1/10

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12
Q

Codeine is usefull becuas

A

Retains activity when given orally

Morphine on the other hand undergoes considerable first pass.

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13
Q

Which side of morphine get glucuronidated in the major metabolic pathway?

A

Left
Morphine-3-glucuronide
Inactive and rapidly excreted.

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14
Q

Minor metabolite of morhpine?

A

Morphine-6-glucuronide
MG6
More potent than morphine and in phase three trials

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15
Q

Two glucuronide metabolites of morhpine tell us that …

A

The six position is not very important in terms of pharmacodynamics

Active whether or not glucuronidated

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16
Q

In general replacing the nitrogen methyl.

A

Analgesic activity decreases as size of n substitutent increases and then rises again. Peak at c 6

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17
Q

Most active n methyl replacement?

A

N-β-phenethylnormorphine

That’s two carbons and a benzene ring - large and lipophilic

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18
Q

Activity falls to minimum with…. Carbons on the n

A

3

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19
Q

Nalorphine structure

A

Propene on the N

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20
Q

Nalorphine action

A

Dual!

a) antagonism at the mu opioid receptor (blocks morhpine)
b) agonism at the kappa opioid receptor (relieves pain)

21
Q

How is the structure and activity of a benzomroph?

A

Benzomorphans have a simplified structure
-removal of one of the rings
-activity is largely retained (compared to morphine)

22
Q

Benzomorphs confirm our ideas at what position?

A

N
N-CH3 - as morhpine
N-ch2ch=c(ch3)2 - kappa ag
N-phenyl ethyl - 3-10x potency of morhpine

23
Q

Pethidine was discovered…

A

By chance

Research into atropine like agents

24
Q

Structural similarity with pethidine and morphine?

A

Piperidine with n-methyl

Gives us more information about the minimum requirements

25
Q

Naloxone is a …

A

Antagonist used for opioid overdose

26
Q

How does the structure of methadone work?

A

Mu agonist
Basic N
Phenyl rings probably interacts in the same place as morphines aryl ring

27
Q

Which isomer of methadone has the acitivty?

A

L mostly

Although D is NMDA ag

28
Q

Methadone stimulates the same receptors as heroin…

How is it different?

A

To similar degrees.
Methadone has much greater lipophilicity than morphine – leads to it being widely distributed around the body. Has a much greater duration of action in vivo. Means it need only be taken once per day and gives it a milder but more protracted withdrawal syndrome.

29
Q

To prove the existence of a receptor you have to…

A

Prove there is specific binding

30
Q

How was [3H]-Naloxone used to show receptor specificity?

A

Technique: Measure binding of a radiolabelled naloxone under two conditions.
1. In presence of large excess of non-radiolabelled naloxone and
2. In presence of large excess of non-radiolabelled naloxone enantiomer.
No difference in labelled naloxone binding = no stereospecific binding
More labelled binding in (2) than in (1) = stereospecific binding

31
Q

If there are receptors there must be,..

A

Endogenous ligands

32
Q

Endogenous ligands for opioid receptor

A

Enkephalins

Tyr-Gly-Gly-Phe-Met(OH) Met-enkephalin
Tyr-Gly-Gly-Phe-Leu(OH) Leu-enkephalin

33
Q

It has been suggested that the tyrosine residue and the tyramine moiety in morphine fulfil the same role but

A

For this to be true it would need to be D tyr
However it does seem likely that morphine and the tyrosine residue of the enkephalins do access the same site in the receptor and interact with the same aspartic acid residue.

34
Q

Reckitt & Colman: Theory (in late 1950’s)

A

was that a more complex compound might fit the ‘analgesic receptor’ but be prevented from fitting the receptor which might be responsible for the unwanted effects of morphine.
(Resp depression/euphoria/analgesia) - they thought they could do this by adding bulk

35
Q

If you study some thine using an animal assay you only get an idea of

A

Activation of receptors

You don’t know if it’s binding with no effect

36
Q

Tertiary alcohol derivatives of the Diels-Alder adduct made using…. And basic structure is based on….

A

Grinyard reaction

Codeine

37
Q

Diels-Alder adduct showed us that

A

The molecule can be too big

Inversion of stereo chem can dramatically affect potency

38
Q

How did we use the Diels-Alder adduct studies to make etorphine (10000 more potent than morphine - animal tranquilizer)

A

The Diels-Alder adduct was based on codeine, we made it based in morphine (change the OMe to OH)

39
Q

Etorphine structure shows a

A

C3H7 produces Lipophilic site for agonist binding

40
Q

orvinol series

A

From the Diels-Alder adduct

We then looked at changing the N

41
Q

Changing the orvinol series 3 position form OH to OMe gives…

A

Higher efficacy but OH is more potent (because higher efficacy for mew)

42
Q

Orvinol N changes, antagonist most significant with…

A

Antagonist activity most evident with propyl, allyl and cyclopropylmethyl substituents

43
Q

Orvinol series

R on the right (the extra bit added) changes how

A

R = Me or Et, get predominant antagonist activity, becomes agonist at n-Pr and n-Bu

44
Q

Orvinol with cyclopropylmethyl on the n and propyl on the extra R in the right. What happened?

A

Good analgesic effects in animals (~1000)uxbut Psychotomimetic

45
Q

Orvinol with cyclopropylmethyl on the n and C(CH3)3 on the extra R in the right. What happened?

A

Bruprenorphine
Mu partial
Kappa anatag
Analgesic and dependance treatment

46
Q

Salvia acts at

A

kappa opioid receptor agonist - we don’t know why

47
Q

Why is buprenorphine so good

A

Very lipophilic with almost irreversible binding to mu… Long duration of action.
Partial agonist activity (not full efficacy) means it has a good safety profile.
Long duration of action helps minimise any withdrawal syndrome after chronic use/treatment.

48
Q

How is buprenorphine admin?

A

Rapidly metabolised therefore sublingual or patch, not oral

49
Q

Revivon

A

Similar structure to buprenorphine

Used to revive large animals as low efficacy

Drug Disco (12 decks)

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