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Med Chem 9 > Opioids > Flashcards

Opioids Flashcards

1
Q

What are the 2 classes of alkaloids?

A

Phenanthrene alkaloids

Benzyl isoquinoline alkaloids

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2
Q

What drugs are phenanthrene alkaloids?

A

Morphine

Codeine (prodrug)

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3
Q

What drugs are benzyl isoquinoline alkaloids?

A

Papaverine

Noscapine

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4
Q

Which of the 2 classes have analgeic effects?

A

Phenanthrene alkaloids only

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5
Q

What is a prodrug?

A

Administered in an inactive or less than fully active form that is through a metabolic process

typically hydrolysis of an ester via esterase activity

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6
Q

We use prodrugs to improve what?

A

ADME

Bioavailability

Side effects profile

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7
Q

Which drugs mentioned in lecture are prodrugs?

A

heroin

codeine

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8
Q

How can you increase activity of morphine?

A
  1. add alkyl group on C17 (longer than ethyl, no longer than 6C)
  2. add phenethyl > activity than benzene ring
  3. saturated double bond between C7 and C8
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9
Q

How can you modify morphine to reduce toxicty while retaining analgesic effects?

A

Add acetyl group to C6 (instread of OH)

Epimerize C6 OH from a to B

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10
Q

How does heroin’s structure differ from morphine?

A

acetyl groups instead of OH at C3 and C6

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11
Q

T/f codeine is more active than morphine

A

false!

Codeine is less active due to methoxy group on C3

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12
Q

Difference between OH at C3 vs C6

A

OH at 3: attached to phenyl group, more acidic, better leaving group = faster hydrolysis

OH at 6: attached to alkyl group

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13
Q

What are the chiral centers located in morphine?

A

5Ra

6Sa

9R

13S

14R

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14
Q

How are the morphine rings fused together?

A

B/C: cis

C/D: trans, C built off equatorial bonds of D

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15
Q

What is the class of flexible opioids?

A

Phenylpiperidine carboxylate class

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16
Q

When do flexible opioids have optimal activity?

A

methyl group on position 1 (N atom)

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17
Q

How are prodine and meperidine different structurally?

A

Prodine: contains methyl to C4 and reverse ester

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18
Q

Features of acyclic analgesic vs morphine

A

tolerance develops more slowly

less euphoria + less withdrawal

highly flexible

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19
Q

What is the best method of fragment based med chem?

A

NMR

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20
Q

Describe fragment based drug design

A

Find a lead fragment via NMR

Optimize fragment by adding groups to it to find what increases or decreases activity to discover new drug compopunds

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21
Q

How do we measure the probability of an effective drug compound?

A

using heavy atom count and free bond energy to calculate ligand efficiency (LE)

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22
Q

What is a pharmacophore?

A

Abstract description of molecular features of a compound

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23
Q

Why are pharmacophores used in drug discovery?

A

Used to show how structurally diverse compounds can bind to the same receptor/enzyme

  • show minimum structure required for ligand receptor/enzyme recognition
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24
Q

What are the pharmacophore features of morphine like derivatives?

A
  1. hydrophobic region
  2. aromatic rings
  3. H donor/acceptors
  4. cations and anions
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25
What does a 2D pharmacophore represent?
Minimum skeletal connecting important binding groups of the compounds
26
Does the 2D pharmacophore provide analgesic effects?
no! requires stereochemical conformation with limited bond rotation
27
What does a 3D pharmacophore represent?
# Define relative positions in space of the important binding groups - gives opiates their analgesic activity
28
What are the endogenous opioids?
1. Enkephalin 2. B-endorphin 3. Dynorphins 4. Endomorphans
29
What are the 2 types of enkephalin?
Met Leu
30
What type of receptors are opioid receptors?
GPCRs
31
List the opioid receptors
Mu Kappa Delta NOP
32
Kappa receptors
spinal analgesia sedation anesthesia
33
Mu receptors
Supra spinal analgesia Euophria/feelings of well being Morphine type physical dependence and withdrawal
34
Delta receptors
Supra spinal analgesia More side effects of tolerance and euphoria
35
NOP receptors
do NOT bind classical opioid peptides/non-peptide agonists with high affinity
36
Pure agonists
potent analgesic and morphine like side effects tolerance dependence respiratory depression
37
Partial agonist
potent analgesic activity with decreased morphine like side effects
38
Pure antagonist
No analgesic effects no morphine side effects used to reverse actions of morphine like activity
39
How can you decrease activity of mu receptor agonists?
Position 3 remove OH, add H substitute methoxy for OH substitiute methyl ester
40
How can you increase the activity of mu receptor agonists?
Position 6: substitute H for OH convert OH to ketone AND add 2 OH at C7 and C8 substitute ester for OH Position 14: add b-OH Position 7 and 8: add di-hydro goups change methyl N to phenethyl N
41
How does the structure of morphinan differ from morphine?
Only 3 chiral centers: 9R, 13S, 14R No E ring and no OH on phenyl group No OH at C6 or double bond between C7 and C8
42
SAR of morphinans
similar as morphine isomers: - levo = more potent than morphine + dextro = no opioid activity but good antitussive activity trans B/C rings = more potent analgesic
43
How does the structure of butorphanols differ from morphine?
No E ring 3 chiral centers (9R, 13S, 14R) b-OH at C14 cyclobutylmethyl ring off of carbon attached to N
44
SAR and activity of butorphanol
5x more potent as analgesic behaves as both weak mu antagonist and strong k agonist
45
How does benzomorphan differ from morphine?
No E or C rings
46
Which sterochemical configuration of benzomorphans is more potent?
Beta: B/C trans
47
Which group can increase analgesic activity of benzomorphans?
CH2-CH2-phenyl group
48
Which R groups change the activity to partial agonist or antagonist of benzomorphans?
cyclopropylmethyl CH2CH = CH2
49
What R group requirements to retain activity of benzomorphans?
1. contain non-H substitutents 2. lower MW alkyl groups: not larger than propyl 3. can be a phenyl group
50
The 3 position in phenylpiperidines is related to which position in morphine and benzomorphan?
Morphine = C14 Benzomorphan = C9 (C11 of benzazocine)
51
Is the alpha or beta position of prodine more potent?
Beta: 3S, 4S (cis)
52
Which position of prodine relates to morphines C14?
3
53
Circle the compound structure modifications that increase potency of meperidine
54
How can you change activity from agonist to angtagonist?
N atom: substitute NCH2CH=CH2 for methyl Reduce C7=C8 to single bond with di-hydros position 6: convert OH to ketone B-OH at C14
55
Which N is most basic?
56
Which CYPs dealkylate methadone?
CYP2C19: R isomer (active) CYP2B6: S isomer (inactive)
57
What 3 active metabolites are produced from methadone?
methadol normethadone dinormethadol
58
How is methadone get to methadol?
Reduced (removal of carbonyl) CYP dealkylated further to normethadol Normethadol = CYP dealkylated to dino
59
How does methadone get to normethadone?
CYP dealkylation One methyl on N compared to 2 with methadone further dealkylated to dino (2H on N)
60
How do we activate the prodrug codeine?
O demethylation which converts it to morphine
61
What process inactivates codeine to norcondeine?
N demethylation (no methyl group on N)
62
What happens if you continue to demethylate norcodeine?
Can produce an active metabolite: O methylation occurs to expose 3OH (normorphine)
63
Which positions are subject to phase II reactions? What are the reactions?
Phenolic 3OH and alcoholic 6OH subject glucuronidation and sulfation
64
Metabolism to activate heroin
1. hydrolysis of 3 position acetyl group to OH (will occur fast) 2. hydrolysis of 6 position acetyl group with occur more slowly than 3
65
Non-selective reaction involves what?
N in b-CNA forming a 3 member ring, expelling Cl
66
Non-selective b-CNA
- Nu from receptor wil lthen attack 3 member ring to open and create covalent bond - this repeats due to 2 Cl side chaines on amine at C6
67
slective b-FNA reaction involves what?
Lys N attacking double bond of R group Form zwitterion intermediate that then results in covalent bond
68
What makes an ideal opioid drug?
1. orally active drug with strong analgesic properties 2. does not cause: tolerance, physical dependence, respiratory depression, emesis

Med Chem 9 (1 decks)

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