receptor sites and drug design
TRANSCRIPT
Organic Lecture Series
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Receptor Sites and Drug Design
Case Study: Opiates use forAnesthesia & analgesia
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PAIN
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The functional groups and their placement in three-dimensional space determines to a large degree a molecule’s biological activity.
The portion of a molecule that determines the biological effects of a drug is called the pharmacophore.
Medicinal Chemistry
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Medicinal Uses for Morphine:
as an adjunct to general anesthesia
in epidural anesthesia or intrathecal analgesia
for palliative care (i.e. to alleviate pain without
curing the underlying reason for it, usually because
the latter is found impossible)
as an antitussive for severe cough;
(Codeine is better)
Codeine
Medicinal Chemistry
Organic Lecture Series
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HO
N CH3
HO
O
Morphine
Codeine(1832)
Oxycodone(1916)
(~1805)
Heroin(1874)
Medicinal Chemistry
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An analgesic (also known as a painkiller) is any member of the group of drugs used to relieve pain (achieve analgesia). The word analgesic derives from Greek an- ("without") and algos ("pain").
A general anesthetic is a drug that brings about a reversible loss or alteration of consciousness.Local anesthesia is any technique to render part of the body insensitive to pain without affecting consciousness.
Medicinal Chemistry
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3
3
3
3
Why do humans have receptor sites for such a complex structure?
Medicinal Chemistry
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Endorphins ("endogenous morphine") are endogenous opioid peptides (discovered in 1974)
An enkephalin is a pentapeptideinvolved in regulating perception of pain in the body
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Opiate antagonist-reversal agentMedicinal Chemistry
Opiate reversal agent (competitive antagonist)-high affinity for μ-receptor site
CH3O
N
O
O
Oxycodone
CH3OH
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Opiate antagonist-reversal agent
Medicinal Chemistry
Opiate reversal agent (blocks “pleasure” centers)-used for treatment of alcohol dependence (alcoholism)& opiate addiction
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33
3
Medicinal Chemistry
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Medicinal Chemistry
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3
2
®
1960-a new opiate, which was based on the piperidinestructure was introduced:
Fentanyl is about 100 X the potency of morphine
Medicinal Chemistry
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3
How does fentanyl and morphine compare?
Medicinal Chemistry
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H2N O
ClPh
BrN O
Ph
K2CO3 NaBH4
NH2
N
NH
PhH O
O O
N
N
PhH
OFentanyl
Commercial Synthesis of Fentanyl Medicinal Chemistry
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N OPh NPh
NH2
KCN HN Ph
CNHCl reflux
NPh
HN Ph
COOH
NPh
HN Ph
CO2Et
EtOH
H3O+
NPh
N Ph
CO2Et
O
Cl
O
NEt3
H2N
NPh
CO2Et
O
H2
Pd(OH)2/C
Anaquest Approach to 4,4-Disubstituted Piperdines:
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H2N
NPh
CO2Et
O
N
N N
N
O
N
N Ph
CO2Et
O
N
N Ph
CO2Et
O
N
N Ph
CO2Et
O
Ph
S
PhBr
K2CO3
Br
K2CO3
BrN
N N
N
O
S
K2CO3
Medicinal Chemistry
Fast acting-less potent than fentanyl
5-10X more potent than fentanyl 10,000 X more potent than morphine
Modify ester-New class of drugs?
Organic Lecture Series
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Organic compounds are transformed to molecules of increasing polarity, then excreted by the kidneys:
A
B
C
B’
inactivation
inactivation
Phase I:Oxidation-reductionHydrolysisDemethylation
activation
inactivation
Phase II:Synthesis (acylation, methylationetc.)Conjugation-covalent bonding with carbohydrates, AA or sulfates
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Medicinal ChemistryMetabolism of Metabolism of PiperidinePiperidine AnalgeticsAnalgetics
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N
N Ph
CO2H
O
N
N Ph
O
OHPh
Known to be inactive metabolite
Ph
N
NPh
O
Ph OH
LAH
Cl
O
NEt3
N
N Ph
O
Ph O
O
O Cl
O
R
NEt3
N
N Ph
O
Ph O OR
O
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N
N Ph
O
Ph O OR
O
N
NPh
O
Ph O
O
Medicinal Chemistry
Pharmacological Profile:Pharmacological Profile:MHP: ED50=0.06 potent analgetic
MHP: >15 min—long acting analgetic
Ki = 3-9 (strength of μ receptor binding)
Anesthesia—2-3 Minutes-short acting
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Esters & Carbonates
Medicinal Chemistry
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Remifentanil is a specific μ-receptor agonist. It is potent & short acting- (1/2 life~4 min)•a reduction in sympathetic nervous system tone, •Slight respiratory depression and analgesia. •dose-dependent decrease in heart rate arterial pressure•respiratory rate and tidal volume near normal
Ultra short acting analgesic