Structure Activity

Relationship
Medicinal Chemistry

• A chemistry-based discipline, involving

aspects of biological, medical and
pharmaceutical sciences.
• It is concerned with the invention, discovery,
design, identification and preparation of
biologically active compounds
Structure Activity Relationship

An approach to identify relationship

between structure related properties
and target activity (chemical, physical,
or biological activity).

❑ Similar structures – similar effects

Structure Activity Relationship

• Predict biological activity

• Drug discovery to guide synthesis of
new compounds
❑ Minor changes on the lead structure

• Change in the size and shape of

the C-skeleton
• Change in the nature and degree
of substitution
• Change in stereochemistry
Change in the size and shape ✓ Increases lipophilicity / increases
❑ Number of methylene groups in chains and rings activity
❑ Increasing or decreasing the degree of unsaturation
✓ For aliphatic compounds →
micelle formation → no selective
❑ introducing or removing a ring system binding
 Applications of SAR

• Pharmacokinetic studies • Toxicity studies

• D-R relationships • Formulation of chemical and

physical properties
• Modification of Drugs
✓ Similar structures QSAR
– similar effects
Quantitative Structure
Activity Relationship
✓ Uses parameters
to describe the
potency
 Ex. Barbiturates

• Malonylurea or 6-hydroxyuracil
• 2,4,6-trioxohexahydropyrimidine
• Lacks CNS depressant activity

General rule:
Lipophilicity,  action,  onset, DoA
Ex. Barbiturates
Thiopental
Analgesics “Drugs that bring about insensibility to
pain without loss of consciousness.”
Analgetics (p.731, 11th Ed)
Who has lower
pain tolerance?
Pain scale
Pain Major classification
• Nociceptive
• Cutaneous
• Somatic
• Visceral
• Inflammatory
• Neuropathic
• Peripheral, Phantom
11th & 12th Ed
 ✓Severe
✓ Lasts when source of pain is
removed
✓N, S, V
Acute Pain ✓Post-op, post-trauma
✓ Burn
✓ Childbirth
✓ Acute HA

12th Ed.
 ✓ Persistent >6 months
✓Chronic malignant
Chronic Pain ✓Cancer, HIV/AIDS
12TH ED.
✓MS
✓Chronic non-malignant
✓OA, RA, migraine
 Analgesic Categories: Therapeutic use
❑ Management of moderate
Opioids / Narcotic analgesics to severe chronic pain

❑ Relief of acute pain

NSAIDS ❑ Management of mild to moderate

pain
❑ Reducing fever
Acetaminophen
❑ Specific for acute and abortive
treatment of migraine and cluster HA
Triptans / Antimigraine
❑ ex. TCA, anticonvulsants, topical
Analgesic adjuvants analgesics

11th & 12th Ed

Is the pain:
Potent opioid 
SEVERE YES Non-opioid or Analgesic Adjuvant

IS THE PAIN PERSISTING OR INCREASING?

Less potent opioid + Non-opioid

MODERATE YES
 Analgesic Adjuvant

IS THE PAIN PERSISTING OR INCREASING?

Non-opioid (NSAID or APAP)

MILD YES  Analgesic Adjuvant
(Non-pharmacological method should also be used)
12th Ed
 Development of Analgesics

Isolation of pure Isolation of

plant Modern pcol Morphine Urea &
techniques Salicylates

Naturally Opioid Methods of

pharmacological
occurring plant receptors testing
drugs
Development of Analgesic activity
organic chemistry of Morphine
11th Ed
 “Opiate”
Opioid Analgesics
“Opioid”
 • Morphine, codeine,
noscapine/narcotine, papaverine
• Thebaine – convulsant | starting
material for other drugs.
• Narceine

Morphine
Opioid peptides

PRECURSOR PROTEINS
TO ENDOGENOUS
OPIOID PEPTIDES
SAR: Enkephalin
SAR: Enkephalin
 
Opioid
Receptors

NOP/
ORL1
Opioid nerve tracts in the CNS
Opioid receptors
 
• Location: Brainstem and medial thalamus
• Endogenous peptides: Endomorphin-1, endomorphin-2, b-
endorphin.
• Exogenous agonist: 4,5-epoxymorphinan, morphinan,
benzomorphan, 4-phenyl/4-anilido piperidines,
diphenylheptanes, dermorphin
 • Analgesia


• Respiratory depression
•  GI motility
• Euphoria
• Feeding
• Release of hormones
 Antagonists

Agonists


 ❑ Anatomic distribution is the same
as MOP and DOP.


❑ Endogenous peptides:
Met-/Leu- enkephalins
DADLE, DSLET, DPDPE
❑ Effects:
❑Initiation of movement
❑ Pain regulation
❑ Euphoria and physical
dependence
 Agonists

Antagonists
 Limbic
Brainstem
Spinal cord

• Prefers peptides with Arg at position 6

• Dysphoria and psychomimetic activities
• Limited analgesic efficacy (esp. in men)
Receptor Endogenous Ligand Action
Ligand precursor

MOR Endorphin and Propiomelanoco Mu-1: Analgesia & dependence

Endomorphin rtin [POMC] Mu-2: Euphoria, dependence, resp
depression, constipation, miosis
Mu-3: vasodilation
KOR Dynorphin Prodynorphin Analgesia, diuresis, and dysphoria

DOR Enkephalin Proenkephalin Analgesia and constipation

NOR Nociceptin / Pre- Analgesia, hyperalgesia

Orphanin pronociceptin (concentration dependent)
ZOR Regulation of development of
normal and tumor cells
 Summary: SAR of Opioid peptides

1. All endogenous opioid peptides have Leu- or Met- enkephalin

as their first 5 AA residues [except for the endomorphins]
2. Tyr1 of all endogenous opioid peptides is essential for activity.
❑Removal of the phenolic OH or the basic N (amino terminus group) → abolish
activity
❑ The Tyr1 free AMINO group may be alkylated to give agonists and antagonists,
BUT must retain its basic nature.

3. Phenyl group of Phe → removal of this group or changing its

distance from Tyr1 → full or substantial loss of activity.
 Summary: SAR of Opioid peptides
4. Enkephalins have low-energy conformations: different conformations – different
affinity | binding to different opioid receptors and subtypes.
5. Replacement of the natural L-AA with D-AA → can make the peptides resistant to
peptidases, that generally rapidly degrade natural endorphins.
6. Conversion of terminal Carboxyl group to an Alcohol or Amide will protect the
compound from carboxypeptidases.
7. Conformational stability of enkephalins is affected by any introduction of D- or L- AA
or bulky groups into its structure.
8. Restricting conformational mobility of peptides make it more receptor-selective, ex.
Gly2 substituted)
How is the pain management for patients who
do not respond to any medical treatment?
 Short bond paper | Intermediate Pad
Handwritten
Tabulate | Key details in bullet form
Act. 5.
Group 1
Drug Monographs 4,5-Epoxymorphinans (7)
Morphinans (2)

QUIZ – May 10, 2023 Group 2

35 points Benzomorphans (1)
Zip grade 4-Phenylpiperidines and 4-Anilidopiperidines (6)
SAR to End of opioid analgesics Diphenylheptans (2)

Group 3
Miscellaneous (1)
Mixed Agonist/Antagonist (3)
Opioid Antagonist (4)