1. Nohad A AlOmari Atrushi
Opioids analgesics By
Nohad A AlOmari Atrushi
28/12/2015

2. Morphine Maximize Minimize
Named after the Greek God, Morpheus (God of dreams)
Good for treating dull, constant pain rather than sharp, periodic pain
Side effects:
Excitation
Euphoria
Nausea
Pupil constriction
Constipation
Tolerance and Dependence
Depression of breathing
Maximize
Minimize

3. 1. Morphine (Lead) target site: CNS SE: serious - An opium alkaloid
- Papaver somniferum
target site: CNS
SE:
serious

4. 2. SAR (peripheral modification) essential for analgesic activity
2.1 The phenolic OH:
essential for analgesic activity
Morphine: Mu, Kappa, Delta Agonist
Codeine (Mu (w), Delta (w))

5. Analgesic, Antipyretics, CNS depressant
Tramadol
(Codeine analogue)
A selective partial mu agonist analgesic with noradrenaline and serotonin reuptake inhibiting properties?
Analgesic, Antipyretics, CNS depressant
less respiratory depression than morphine

6. SAR - The phenol moiety Notes
Codeine is metabolised in the liver to morphine.
The activity observed is due to morphine.
Codeine is used for mild pain and coughs
Weaker analgesic but weaker side effects.
mor053 .WAV
Conclusion
Masking phenol is bad for activity

7. SAR - The phenol moiety RO R=Ac 3-Acetylmorphine Decreased activity O
NMe O RO HO H
R=Ac 3-Acetylmorphine
Decreased activity
mor053 .WAV
Acetyl masks the polar phenol group
Compound crosses the blood brain barrier more easily
Acetyl group is hydrolysed in the brain to form morphine

8. unessential for analgesic activity
2.2 The 6-OH:
increase lipophilicity

9. SAR - The 6-alcohol HO R=Me Heterocodeine 5 x activity O NMe RO H
mor053 .WAV

10. SAR - The 6-alcohol HO O NMe mor053 .WAV
Activity increases due to reduced polarity
Compounds cross the blood brain barrier more easily
6-OH is not important for binding

11. SAR - The 6-alcohol HO R=Ac 6-Acetylmorphine Increased activity (4x) O
NMe O HO RO H
R=Ac 6-Acetylmorphine
Increased activity (4x)
mor053 .WAV
Acetyl masks a polar alcohol group making it easier to cross BBB
Phenol group is free and molecule can bind immediately
Dependence is very high
6-Acetylmorphine is banned in many countries

12. SAR - The 6-alcohol and phenol
NMe O RO H
R=Ac Heroin
Increased activity (2x)
mor053 .WAV
Increased lipid solubility
Heroin crosses the blood brain barrier more quickly
Acetyl groups are hydrolysed in the brain to generate morphine
Fast onset and intense euphoric effects

13. SAR - Double bond at 7,8 HO Dihydromorphine Increased activity O NMe
mor053 .WAV
The alkene group is not important to binding

14. SAR - Nitrogen HO No activity O CHMe Nitrogen is essential to binding
mor053 .WAV
Nitrogen is essential to binding

15. SAR - Methyl group on nitrogen
NR= NH Normorphine
Reduced activity (25%) NR O HO H O
NR= NMe + -
No activity
NR= N+Me2
mor053 .WAV
Normorphine is more polar and crosses the BBB slowly
Ionized molecules cannot cross the BBB and are inactive
Ionized structures are active if injected directly into brain
R affects whether the analogue is an agonist or an antagonist

16. SAR - Stereochemistry HO HO O O NR NR Mirror image of morphine
mor053 .WAV
Mirror image of morphine
No activity
10% activity
Changing the stereochemistry is detrimental to activity

17. SAR - Important binding interactions
HBD or HBA
NMe O HO H
van der Waals
mor053 .WAV
Ionic
(N is protonated)

18. PHARMACOPHORE VDW HBD/HBA Ionic
This allows a pharmacophore to be identified

19. Morphine - SAR Phenolic OH   Aromatic ring Required Required
 N-methyl group
Ether bridge 
Required
Not Required
 Double bond at 7-8
6-alcohol 
Not Required
Not Required

20. Morphine – Drug DissectionA
Loss of activity
Activity retained E D B C
Morphinans
Methadone
Benzomorphans
4-phenylpiperidines

21. -Acetylmorphine > Heroin > Morphine
Morphine ph-OH alc-OH
-Acetylmorphine 3-OH 6-OAc
Heroin -OAc -OAc
-Acetylmorphine > Heroin > Morphine

22. unessential for analgesic activity
2.3 The double bond at 7-8:
unessential for analgesic activity

23. E E U U U
2.4 The N-methyl group:
N essential (ioized) but methyl substituent unessential for analgesic activity
in vivo

24. 2.5 The aromatic ring: essential for analgesic activityU U U U
2.5 The aromatic ring: essential for analgesic activity
2.6 The ether bridge: unessential for analgesic activity

25. 2.7 Stereochemistry: essential for analgesic activity

26. of SAR (peripheral modification)
2.8.1 essential
phenolic OH Ar
ionized nitrogen center
Stereoisomer analgesic activity
2.8.2 unessential: The ether bridge, -OH, E
2.8 Conclusion
of SAR (peripheral modification) E U U U U
H-bond
Van der waals
Ionic bonds

27. morphine codeine
6- acetylmorphine heroin
hydromorphone hydrocodone
oxymorphone oxycodone

28. 3. Development of morphine analogues
- drug extension
- simplification
- rigidification

29. 3.1 Drug extension - Substrate Receptor - Binding group phenolic
OH, Ar., N

30. Morphine N-CH3 CH2CH2Ph N: A > Amorphine RU R
Morphine U U U
N-CH3
R = Me Et Pr : Agonist decreases, Antagonisim increases
Bu : Zero Activity Hexyl :Agonists
CH2CH2Ph : 14 x Activity wrt morphine
CH2CH2Ph N: A > Amorphine

31. 3.1.2 N-allyl gr. or N-cyclopropylmethelene:
antagonist or mixed action
Compound group Agonist Partial agonist Antagonist Note
Naloxone N-allyl Mu, Kappa Delta opioids
- No serious opioids SE
Nalorprine N-allyl Sigma Kappa Mu, Delta Mixed action Low additive
- Hallucinogenic

32. Naloxone
Naltrexone
Nalmefene
Nalorphine

33. 3.2 Simplification or drug dissection
Carbon skeleton ?
3.2.1 ring E: essential E E
Morphine

34. 3.2.2 ring D: Unessential: Morphinans
Morphine
3.2.2 ring D: Unessential: Morphinans
- CH2CH2Ph N: A > Amorphine : Higher toxicity
- allyl gr. N : Antagonist

35. Morphine Analogues - Morphinans
How it’s related:
Ether bridge removed
Activity:
5x that of morphine
Advantage:
It can be taken orally
Lasts longer
Easier to synthesize
Side effects:
High toxicity, comparable dependence
Marketed as Levo-Dromoran®
Levorphanol

36. Conclusion of Morphinans
1. ring D is not essential
2. more active, longer acting but more SE than morphine: Levorphanol: orally active
3. Morphinans and Morphine: reacting with the same receptors in the same way.

37. 3.2.3 ring C&D: unessential: Benzomorphans
Morphine U
3.2.3 ring C&D: unessential: Benzomorphans
CH2CH2Ph บน N:
A > Amorphine
allyl gr. N:
Mixed action

38. Comparing pentazocine with nalorphine?
Compound group Agonist Partial agonist Antagonist Note
Pentazocine N-allyl Sigma Kappa Mu, Delta Mixed action Low additive
- Hallucinogenic
Comparing pentazocine with nalorphine?
Unfortunately: hallucinogenic SE: Sigma Agonist

39. Morphine Analogues - Benzomorphans
How it’s related
Rings C and D removed
Activity
4x + that of morphine
Advantages
No addictive properties
Does not depress breathing
Lasts longer
Side effects :Hallucinogenic
Marketed as Prinadol, Norphen
Fortal, Talwin NX
Phenazocine
Pentazocine

40. Conclusion of Benzomorphans
1. ring C, D are not essential
analgesia and addiction are not necessarily coexistent
3. reasonable analgesic activity, less addictive liability, less tolerance
simpler to synthesize
5. phenazocene, pentazocine
6. hallucinogenic effect

41. 3.2.4 ring B&C&D: unessential: 4-phenylpiperidine
Morphine U
3.2.4 ring B&C&D: unessential: 4-phenylpiperidine

42. more potent than morphine because of more lipophilicity

43. Morphine Analogues – 4-phenylpiperidines
Fentanyl
How it’s related:
Rings B,C,D removed
Activity:
100x that of morphine
Advantages:
Cross BBB efficiently
Really easy to make
Rapid onset, short duration
Can be administered any way (IV, oral, transdermal, buccal)
Fentanyl

44. Morphine Analogues – 4-phenylpiperidines
Used for:
Anesthesia
Chronic pain management
Side effects:
Sudden respiratory depression
More addictive than heroin
Less euphoria, more sedation
Marketed as:
Sufenta (used in ♥ surgery)
Carfentanil (used in vet practice)
“Percopop”, OxyContin, “magic” (heroin/cocaine)

46. Conclusion of 4-Phenylpiperidine
1. ring B, C, D are not essential
2. retain SE: addition, respiratory depression
3. faster acting, shorter duration of action
4. interact with the analgesic receptors in a different manner to morphine
5. meperidine (pethidine), fentanyl, carfentanil, lofentanil, sufentanyl, alfentanil, remifentanil

47. 3.2.5 ring B&C&D&E: Unessential: Diphenylpropylamine
Morphine U
3.2.5 ring B&C&D&E: Unessential: Diphenylpropylamine
1. comparable in activity to morhine
2. orally active
3. retains morphines-like SE
- less severe sedation, euphoria, withdrawal, emetic, constipation
4. a substitute for morphine or heroin
methadone

48. Morphine Analogues - Methadone
How its related:
Rings B,C,D,E opened
Activity
< Morphine
Used to:
With addicts off heroine or morphine
Advantages:
Can be given orally
Less severe side effects
Marketed as Dolophine®, Amidone®, Methadose®

49. Morphine analogues - Naltrexone
How it’s related:
Cyclopropylmethylene added to morphine
Activity:
None?!
Morphine antagonists
Used to treat:
Morphine overdose
Heroin addicts post-rehab
Advantages:
No side effects
Marketed as: Revia, Depade, Vivitrol
Naltrexone
Nalorphine

50. Conclusion of Simplification
Morphinans:
1. ring D is not essential
2. more active, loger acting but more SE than morphine: Levorphanol: orally active
3. Morphinans and Morphine: reacting with the same receptors in the same way.
Benzomorphans:
1. ring C, D are not essential
2. analgesia and addiction are not necessarily coexistent
3. reasonable analgesic activity, less addictive liability, less tolerance simpler to synthesize
4. phenazocene, pentazocine
5. hallucinogenic effect

51. 4-Phenylpiperidine
1. ring B, C, D are not essential
2. retain SE: addition, respiratory depression
3. faster acting, shorter duration of action
4. interact with the analgesic receptors in a different manner to morphine
5. meperidine (pethidine), fentanyl, carfentanil, lofentanil, sufentanyl, alfentanil, remifentanil
Diphenylpropylamine: methadone
1. ring B, C, D, E are not essential
2. comparable in activity to morhine
3. orally active
4. retains morphines-like SE:
- less severe sedation, euphoria, withdrawal, emetic, constipation
5. a substitute for morphine or heroin

52. 3.3 Rigidification Morphine Buprenorphine Etorphine
group Agonist Partial agonist Antagonist
Etorphine Mu, Kappa, Sedative D Delta
Buprenorphine N-cyclopropyl Mu Kappa, Delta - Mixed action
methylene fentanyl

53. Non-opioids receptors
.1. Mu: Mu1:
Mu2:
. 2. Kappa:, Sedation
3. Delta: + ?
Sigma: + Psychotomimetic: Hallucinogenic effect
Opioids receptors
- Morphine
- Nalorprine
- Pentazocine
- Buprenorphine
Non-opioids receptors

54. Opioid Receptors Receptor-binding motif: Phenol OH Aromatic ring
Amine group

55. An ideal analgesic agent?
Orally active
Mu:
Kappa:
Sigma:
antagonist
agonist
No activity

56. Most strongly binds morphine
Opioid Receptors
Most strongly binds morphine
Receptor type
Location
Effects μ
Brain, spinal cord
Analgesia, Respiratory depression, euphoria, addiction, ALL pain messages blocked κ
Analgesia, sedation, all non-thermal pain messages blocked δ
Brain
Analgesia, antidepression, dependence
Best bet for a safe analgesic

57. Receptor binding - μ μ K+ K+ K+ K+
Opening of the K+ channel hyperpolarizes the membrane
Action potential not sent
Ca+2 not released
Reduces neurotransmitter release
Morphine μ K+ K+
Hyper-polarized! K+ K+

58. Receptor Binding - κ κ Ca+2 Ca+2 Ca+2 Ca+2
Binding causes closing of Ca+2 channels
Neurotransmitters not released
Pain message not sent
Morphine κ
Ca+2
Ca+2
Ca+2
Ca+2

59. Why you feel “happy”

60. Endogenous Opioid Peptides
Your body’s natural painkillers
Have a preference for the δ-receptor
Alternative method of pain relief  inhibit the peptidases that degrade them  thiorphan (still new)
3 types of EOPs:
Enkephalins
Dynorphins
Endorphins
Met-enkephalin

61. Partial Kappa Agonist

62. 5. Theory: Agonists, Partial agonists, Antagonists
Receptor binding sites
1)Essential binding sites: phenolic-OH, Ar, ionized N center
2) Agonist binding sites (Hydrophobic)
3) Antagonist binding sites (Hydrophobic)

63. Agonists

64. 5.2 Partial agonist

65. Antagonists

66. Agonists and Antagonists
Equatorial Antagonist binding area
Axial Agonist binding area

67. Conclusion of Opioids analgesics
and antagonists
1. morphine
2. peripheral modification:
codeine, 6- acetylmorphine, heroin, hydromorphone, hydrocodone,
oxymorphone, oxycodone
3. drug extention:
naloxone, naltrexone, nalmefene, nalorphine

68. 4. simplification Morphinans: 1. ring D is not essential
2. more active, loger acting but more SE than morphine: Levorphanol: orally active
3. Morphinans and Morphine: reacting with the same receptors in the same way.
Benzomorphans:
1. ring C, D are not essential
2. analgesia and addiction are not necessarily coexistent
3. reasonable analgesic activity, less addictive liability, less tolerance simpler to synthesize
4. phenazocene, pentazocine
5. hallucinogenic effect

69. 4-Phenylpiperidine
1. ring C, D, E are not essential
2. retain SE: addition, respiratory depression
3. faster acting, shorter duration of action
4. interact with the analgesic receptors in a different manner to morphine
5. meperidine (pethidine), fentanyl, carfentanil, lofentanil, sufentanyl, alfentanil, remifentanil
Diphenylpropylamine: methadone
1. ring B, C, D, E are not essential
2. comparable in activity to morhine
3. orally active
4. retains morphines-like SE:
- less severe sedation, euphoria, withdrawal, emetic, constipation
5. a substitute for morphine or heroin

70. 5. rigidification
etorphine, buprenorphine

71. SIDE NOTE: Other factors important to receptor binding:
Stereochemistry
Enantiomers of many of the analogues were tested for analgesic activity. Overall, they didn’t have any.
Rigidification
Used to maintain active formation and eliminate alternative conformations
Increases selectivity for receptors

72. Selective K-agonist (Not Specific)
The Future
Kappa agonist:
Selective K-agonist (Not Specific)

73. The Future Find an agonist that solely binds to the κ- receptor
Explore the μ-receptor subtypes further to see if any of them don’t cause harmful side effects
Peripheral opiate receptors – avoid BBB obstacle
Block postsynaptic receptors involved in the transmission of a pain signal
GABA
Agonists for the cannabinoid receptor

74. 2. Selective Mu1 agonist
3. Peripheral opiate receptor agonist

75. Morphine Analogues - Codeine
How it’s related
Methyl ether of morphine
Activity
20% that of morphine
Pro-drug of morphine
Metabolized by O-demethylation in the liver to make morphine
Codeine

76. Morphine Analogues - Codeine
Treats:
Moderate pain
Coughs
diarrhea
Marketed as:
Tylenol® with Codeine
Hydrocodone
Vicodin® (with Thebaine)

77. Morphine Analogues - Heroine
How it’s related:
3,6-diacetyl ester of morphine
Activity:
2x that of morphine
Polar groups are hidden, making it easy to cross BBB.
Treats:
Pain in terminally ill patients
Side effects
Euphoria, addiction, tolerance
Marketed as:
Heroin, “dope”
Heroine

78. Morphine Analogues - Heroine
6-acetylmorphine
How it’s related:
6-acetyl of morphine
Activity
4x that of morphine!
Polarity decreased, but phenol is ready to bind receptor
Side effects: Very potent!!
Euphoria, addiction, etc.
Marketed as:
NOTHING! It’s banned from production in many countries
6-acetylmorphine

79. References http://www.opioids.com
Patrick, G. L An introduction to medicinal chemistry. Oxford: Oxford University Press.
Wolff, M. E Burger’s medicinal chemistry and drug discovery. vol. 1. 5th ed. New York: John Wiley & Sons.