The Organic Chemistry of Drug Design and Drug Action

1
The Organic Chemistry of Drug Design and Drug
Action

• Chapter 8
• Prodrugs and Drug Delivery Systems

2
Prodrugs and Drug Delivery Systems
Prodrug - a pharmacologically inactive compound
that is converted to an active drug by a
metabolic biotransformation Ideally, conversion
occurs as soon as the desired goal for designing
the prodrug is achieved.

• Prodrugs and soft drugs are opposite
• a prodrug is inactive - requires metabolism to
  give active form
• a soft drug is active - uses metabolism to
  promote excretion
• A pro-soft drug would require metabolism to
  convert it to a soft drug

3
Utility of Prodrugs
1. Aqueous Solubility - to increase water
solubility so it can be injected in a small
volume 2. Absorption and Distribution - to
increase lipid solubility to penetrate membranes
for better absorption and ability to reach site
of action 3. Site Specificity - to target a
particular organ or tissue if a high
concentration of certain enzymes is at a
particular site or append something that directs
the drug to a particular site
4
Utility of Prodrugs (contd)
4. Instability - to prevent rapid metabolism
avoid first-pass effect 5. Prolonged Release - to
attain a slow, steady release of the drug 6.
Toxicity - to make less toxic until it reaches
the site of action 7. Poor Patient Acceptability
- to remove an unpleasant taste or odor gastric
irritation 8. Formulation Problems - to convert a
drug that is a gas or volatile liquid into a solid
5
Types of Prodrugs Drug Latentiation - rational
prodrug design
I. Carrier-linked prodrug A compound that
contains an active drug linked to a carrier group
that is removed enzymatically A. bipartate -
comprised of one carrier attached to drug B.
tripartate - carrier connected to a linker that
is connected to drug C. mutual - two, usually
synergistic, drugs attached to each other
II. Bioprecursor prodrug A compound metabolized
by molecular modification into a new compound,
which is a drug or is metabolized further to a
drug - not just simple cleavage of a group from
the prodrug
6
Protecting Group Analogy for the Concept of
Prodrugs
Scheme 8.1
analogous to
carrier-linked
analogous to
bioprecursor
Keep in mind that a prodrug whose design is based
on rat metabolism may not be effective in humans.
7
Mechanisms of Prodrug ActivationCarrier-Linked
Prodrugs
Most common activation reaction is hydrolysis.
8
Ideal Drug Carriers
1. Protect the drug until it reaches the site of
action 2. Localize the drug at the site of
action 3. Allow for release of drug 4. Minimize
host toxicity 5. Are biodegradable, inert, and
nonimmunogenic 6. Are easily prepared and
inexpensive 7. Are stable in the dosage form
9
Carrier Linkages for Various Functional
GroupsAlcohols, Carboxylic Acids, and Related
Groups

• Most common prodrug form is an ester
• esterases are ubiquitous
• can prepare esters with any degree of
  hydrophilicity or lipophilicity
• ester stability can be controlled by appropriate
  electronic and steric manipulations

10
Prodrugs for Alcohol-Containing Drugs
Table 8.1 Ester analogs as prodrugs can affect
lipophilicity or hydrophilicity
11

• To accelerate hydrolysis rate
• attach an electron-withdrawing group if a base
  hydrolysis mechanism is important
• attach an electron-donating group if an acid
  hydrolysis mechanism is important

• To slow down hydrolysis rate
• make sterically-hindered esters
• make long-chain fatty acid esters

12
Another Approach to Accelerate HydrolysisIntramol
ecular hydrolysis of succinate esters
Scheme 8.2
13
Enolic hydroxyl groups can be esterified as well.
antirheumatic agent
14
Carboxylic Acid-Containing GroupsEsterify as
with alcohols
15
Maintaining Water Solubility of Carboxylate
Prodrugs
Can vary pKa by appropriate choice of R and R?
16
Prodrugs for Phosphate- or Phosphonate-Containing
Drugs
17
Amine Prodrugs
Table 8.2
Amides are commonly not used because of
stability Activated amides (low basicity amines
or amino acids) are effective pKa of amines can
be lowered by 3 units by conversion to N-Mannich
bases (X CH2NHCOAr)
18
N-Mannich base (R CH2NHCOPh) has a log D7.4 two
units greater than the parent compound.
19
Another approach to lower pKa of amines and make
more lipophilic.
Imine (Schiff base) prodrug
hydrolyze imine and amide to GABA inside brain
anticonvulsant
20
A Reductive Carrier-Linked Prodrug Approach
Scheme 8.3
21
Prodrugs of Sulfonamides
A water soluble prodrug of the anti-inflammatory
drug valdecoxib (8.9) has been made (8.10).
22
Prodrug Analogs of Carbonyl Compounds
Table 8.3
imines
oximes
ketals
Acetals or ketals can be made for rapid
hydrolysis in the acidic medium of the GI tract.
23
Examples of Carrier-Linked Bipartate Prodrugs
24
Prodrug Stability Properties
Choice of hydrolytic prodrug group The group
must be stable enough in water for a shelf life
of gt 2 years (13 year half-life), but must be
hydrolyzed in vivo with a half-life lt 10 minutes.
Therefore, in vivo/in vitro lability ratio about
106.
25
Prodrug for Increased Water Solubility
Prodrug forms
for aqueous injection or opthalmic use
poor water solubility
corticosteroid
26
To avoid formulation of etoposide with detergent,
PEG, and EtOH (used to increase water
solubility), it has been converted to the
phosphate prodrug.
27
Prodrug for Improved Absorption Through Skin
corticosteroids - inflammation, allergic,
pruritic skin conditions
28
Better absorption into cornea for the treatment
of glaucoma
The cornea has significant esterase activity
29
Prodrug for Site Specificity
Bowel sterilant
(administer rectally)
Prodrug R Ac (administered orally) Hydrolyzed
in the intestines
30
Prodrug for Site Specificity
The blood-brain barrier prevents hydrophilic
molecules from entering the brain, unless
actively transported. The anticonvulsant drug
vigabatrin (see Chapter 5) crosses poorly. A
glyceryl lipid (8.17, R linolenoyl) containing
one GABA ester and one vigabatrin ester was 300
times more potent in vivo than vigabatrin.
31
Site Specificity Using Enzymes at the Site of
Action
Phosphatase should release the drug selectively
in tumor cells. This approach has not been
successful because the prodrugs are too polar,
enzyme selectivity is not sufficient, or tumor
cell perfusion rate is poor.
32
Enzyme-Prodrug Therapies
For selective activation of prodrugs in tumor
cells Two steps 1. incorporate a
prodrug-activating enzyme into a target tumor
cell 2. administer a nontoxic prodrug which is a
substrate for the exogenous enzyme incorporated
33
Criteria for Success with Enzyme-Prodrug Therapies

• The prodrug-activating enzyme is either nonhuman
  or a human protein expressed poorly
• 2. The prodrug-activating enzyme must have high
  catalytic activity
• 3. The prodrug must be a good substrate for the
  incorporated enzyme and not for other endogenous
  enzymes
• 4. The prodrug must be able to cross tumor cell
  membranes
• 5. The prodrug should have low cytotoxicity and
  the drug high cytotoxicity
• 6. The activated drug should be highly diffusable
  to kill neighboring nonexpressing cells
  (bystander killing effect)
• 7. The half-life of the active drug is long
  enough for bystander killing effect but short
  enough to avoid leaking out of tumor cells

34
Antibody-Directed Enzyme Prodrug Therapy (ADEPT)
An approach for site-specific delivery of cancer
drugs. Phase One An antibody-enzyme conjugate is
administered which binds to the surface of the
tumor cells. The antibody used has been targeted
for the particular tumor cell. The enzyme chosen
for the conjugate is one that will be used to
cleave the carrier group off of the prodrug
administered in the next phase. Phase Two After
the antibody-enzyme has accumulated on the tumor
cell and the excess conjugate is cleared from the
blood and normal tissues, the prodrug is
administered. The enzyme conjugated with the
antibody at the tumor cell surface catalyzes the
conversion of the prodrug to the drug when it
reaches the tumor cell.
35
ADEPT
Advantages 1. Increased selectivity for targeted
cell 2. Each enzyme molecule converts many
prodrug molecules 3. The released drug is at the
site of action 4. Concentrates the drug at the
site of action 5. Demonstrated to be effective at
the clinical level
Disadvantages 1. Immunogenicity and rejection of
antibody-enzyme conjugate 2. Complexity of the
two-phase system and i.v. administration 3.
Potential for leakback of the active drug
36
An example is carboxypeptidase G2 or alkaline
phosphatase linked to an antibody to activate a
nitrogen mustard prodrug.
Scheme 8.4
Humanization of antibodies minimizes
immunogenicity. Note the prodrug-activating
enzyme is a bacterial enzyme.
37
Antibody-Directed Abzyme Prodrug Therapy (ADAPT)
Instead of using a prodrug-activating enzyme, a
humanized prodrug-activating catalytic antibody
(abzyme) can be used. Ideally, the abzyme
catalyzes a reaction not known to occur in
humans, so the only site where the prodrug could
be activated is at the tumor cell where the
abzyme is bound. Antibody 38C2 catalyzes
sequential retro-aldol and retro-Michael
reactions not catalyzed by any known human
enzyme. Found to be long-lived in vivo, to
activate prodrugs selectively, and to kill colon
and prostate cancer cells.
38
Abzyme 38C2 Activation of a Doxorubicin Prodrug
Scheme 8.5
39
Gene-Directed Enzyme Prodrug Therapy (GDEPT)Also
known as suicide gene therapy
A gene encoding the prodrug-activating enzyme is
expressed in target cancer cells under the
control of tumor-selective promoters or by viral
transfection. These cells activate the prodrug as
in ADEPT.
Scheme 8.6
40
Prodrug for Stabilityprotection from first-pass
effect
Oral administration has lower bioavailability
than i.v. injection.
antihypertension
plasma levels 8 times that with propranolol
41
Prodrugs for Slow and Prolonged Release
1. To reduce the number and frequency of doses 2.
To eliminate night time administration 3. To
minimize patient noncompliance 4. To eliminate
peaks and valleys of fast release (relieve strain
on cells) 5. To reduce toxic levels 6. To reduce
GI side effects
Long-chain fatty acid esters hydrolyze
slowly Intramuscular injection is used also
42
Sedative/tranquilizer/antipsychotic
slow release
inject i.m.
Antipsychotic activity for about 1 month
43
Prodrugs to Minimize Toxicity
Many of the prodrugs just discussed also have
lower toxicity. For example, epinephrine (for
glaucoma) has ocular and systemic side effects
not found in dipivaloylepinephrine.
44
Prodrug to Increase Patient Acceptance
The antibacterial drug clindamycin (8.28) is
bitter and not well tolerated by
children. Clindamycin palmitate is not bitter.
Either not soluble in saliva or does not bind to
the bitter taste receptor or both.
45
Prodrug to Eliminate Formulation Problems
Formaldehyde is a gas with a pungent odor that is
used as a disinfectant. Too toxic for direct use.
It is a stable solid that decomposes in aqueous
acid. The pH of urine in the bladder is about
4.8, so methenamine is used as a urinary tract
antiseptic. Has to be enteric coated to prevent
hydrolysis in the stomach.
46
Areas of Improvement for Prodrugs

• site specificity
• protection of drug from biodegradation
• minimization of side effects

47
Macromolecular Drug Delivery
To address these shortcomings, macromolecular
drug delivery systems have been developed.
A bipartate carrier-linked prodrug in which the
drug is attached to a macromolecule, such as a
synthetic polymer, protein, lectin, antibody,
cell, etc. Absorption/distribution depends on the
physicochemical properties of macromolecular
carrier, not of the drug. Therefore, attain
better targeting. Minimize interactions with
other tissues or enzymes. Fewer metabolic
problems increased therapeutic index.
48
Disadvantages of Macromolecular Delivery Systems

• Macromolecules may not be well absorbed
• Alternative means of administration may be
  needed (injection)
• Immunogenicity problems

49
Macromolecular Drug Carriers
Synthetic polymers
Aspirin linked to poly(vinyl alcohol) has about
the same potency as aspirin, but less toxic.
50
Steric Hindrance by Polymer Carrier
poly(methacrylate)
to enhance water solubility
testosterone
No androgenic effect
Polymer backbone may be sterically hindering the
release of the testosterone.
51
A spacer arm was added, and it was as effective
as testosterone.
to enhance water solubility
52
Poly(?-Amino Acid) Carriers
poly(L-glutamine)
spacer
norethindrone - contraceptive
Slow release over nine months in rats
53
General Site-Specific Macromolecular Drug
Delivery System
either hydrophilic or hydrophobic
for site specificity
54
Site-Specific Delivery of a Nitrogen Mustard
poly(L-Glu)
spacer arm
antibody from rabbit antiserum against mouse
lymphoma cells
water-solubilizing
All 5 mice tested were alive and tumor free after
60 days (all controls died). Also, therapeutic
index greatly enhanced (40 fold).
55
Tumor Cell Selectivity
Drug attached to albumin (R albumin)
Tumor cells take up proteins rapidly. Proteins
broken down inside cells, releasing the drug.
Shown to inhibit growth of Ectomelia virus in
mouse liver, whereas free inhibitor did not.
antitumor
56
Antibody-Targeted Chemotherapy
calicheamicin, except as disulfide instead of
trisulfide
Scheme 8.7
spacer
humanized
Does not release calicheamicin nonenzymatically. E
xhibits no immune response.
57
Tripartate Drugs(Self-immolative Prodrugs)
A bipartate prodrug may be ineffective because
the linkage is too labile or too stable. In a
tripartate prodrug, the carrier is not attached
to the drug rather, to the linker. Therefore,
more flexibility in the types of functional
groups and linkages that can be used, and it
moves the cleavage site away from the
carrier. The linker-drug bond must cleave
spontaneously (i.e., be self-immolative) after
the carrier-linker bond is broken.
58
Tripartate Prodrugs
Scheme 8.8
59
Typical Approach
Scheme 8.9
60
Tripartate Prodrugs of Ampicillin
Poor oral absorption (40) Excess antibiotic may
destroy important intestinal bacteria used in
digestion and for biosynthesis of
cofactors. Also, more rapid onset of resistance.
antibacterial
Various esters made were too stable in humans
(although they were hydrolyzed in rodents) -
thought the thiazolidine ring sterically hindered
the esterase.
61
Tripartate Prodrugs of Ampicillin
Scheme 8.10
98-99 absorbed Ampicillin is released in lt 15
minutes
62
Reversible Redox Drug Delivery System to the CNS
Scheme 8.11
hydrolysis activated
hydrolysis deactivated
hydrophilic drug
electron-withdrawing hydrophilic
electron-donating, lipophilic carrier
Passive diffusion of 8.47 into the brain active
transport of 8.49 out of the brain
XH of the drug is NH2, OH, or COOH
If oxidation occurs before it gets into the
brain, it cannot cross the blood-brain barrier.
63
When the drug is a carboxylic acid, a
self-immolative reaction also can be used.
Scheme 8.12
64
Example of Tripartate Redox Drug Delivery
?-Lactams are too hydrophilic to cross the
blood-brain barrier effectively.
Scheme 8.13
High concentrations of ?-lactams delivered into
brain.
65
Another Tripartate Prodrug for Delivery of
Antibacterials
Permeases are bacterial transport proteins for
uptake of peptides.
Scheme 8.14
Only L,L-dipeptides are active
66
Mutual Prodrugs
A bipartate or tripartate prodrug in which the
carrier is a synergistic drug with the drug to
which it is linked.
Antibacterial ampicillin
?-lactamase inactivator penicillanic acid sulfone
Hydrolysis gives 111 ampicillin penicillanic
acid sulfone formaldehyde
67
Ideal Mutual Prodrugs

• Well absorbed
• Both components are released together and
  quantitatively after absorption
• Maximal effect of the combination of the two
  drugs occurs at 11 ratio
• Distribution/elimination of components are
  similar

68
Bioprecursor Prodrugs
Carrier-linked prodrugs largely use hydrolytic
activation Bioprecursor drugs mostly use
oxidative or reductive activation The
metabolically-activated alkylating agents
discussed in Chapter 6 are actually examples of
bioprecursor prodrugs.
69
Protonation ActivationDiscovery of Omeprazole
Cimetidine and ranitidine (Chapter 3) reduce
gastric acid secretion by antagonizing the H2
histamine receptor. Another way to lower gastric
acid secretion is by inhibition of the enzyme
H,K-ATPase (also called the proton pump), which
exchanges protons for potassium ions in parietal
stomach cells, thereby increasing stomach acidity.
70
Lead Discovery
Lead compound found in a random screen.
Liver toxicity observed thought to be because of
the thioamide group.
71
Lead Modification
Related analogs made, and 8.61 had good
antisecretory activity.
Modification gave 8.62 with high activity.
The sulfoxide (8.63) was more potent, but it
blocked iodine uptake into the thyroid.
72
Lead Modification (contd)
Modification of 8.63 gave 8.64 having no iodine
blockage activity.
Picoprazole shown to be an inhibitor of
H,K-ATPase. SAR of analogs indicated
electron-donating groups on the pyridine ring
were favorable. Increased inhibition of
H,K-ATPase. Best analog was omeprazole (8.65).
73
The pKa of the pyridine ring of omeprazole is
about 4, so it is not protonated and able to
cross the secretory canaliculus of the parietal
cell. The pH inside the cell is below 1, so this
initiates the protonation reaction below.
Scheme 8.16
Formation of 8.66 leads to covalent
attachment. Omeprazole also inhibits isozymes of
carbonic anhydrase, another mechanism for
lowering gastric acid secretion.
74
Hydrolytic Activation
Hydrolysis can be a mechanism for bioprecursor
prodrug activation, if the product requires
additional activation.
Scheme 8.17
antitumor agent
prodrugs of leinamycin
75
Hydrolysis of these analogs gives an intermediate
that reacts further to the activated form.
this was synthesized and gave 8.74 as well as DNA
cleavage
increased stability over leinamycin
Scheme 8.18
76
Elimination Activation
Scheme 8.19
potent inhibitor of dihydroorotate dehydrogenase
rheumatoid arthritis drug
Inhibition of dihydroorotate dehydrogenase blocks
pyrimidine biosynthesis in human T lymphocytes.
77
Oxidative ActivationN-Dealkylation
Scheme 8.20
78
O-Dealkylation
Analgesic activity of phenacetin is a result of
O-dealkylation to acetaminophen.
79
Oxidative Deamination
Neoplastic (cancer) cells have a high
concentration of phosphoramidases, so hundreds of
phosphamide analogs of nitrogen mustards were
made for selective activation in these cells.
Scheme 8.21
Cyclophosphamide was very effective, but it
required liver homogenates (contains P450) for
activation. Therefore oxidation is required, not
hydrolysis.
isolated
80
N-Oxidation
identified
advanced Hodgkins disease
Scheme 8.22
identified
81
N-Oxidation
Pralidoxime chloride is an antidote for nerve
poisons. It reacts with acetylcholinesterase
that has been inactivated by organophosphorus
toxins.
82
To increase the permeability of pralidoxime into
the CNS, the pyridinium ring was reduced (8.92).
oxidation in brain
Similar to the reversible redox drug delivery
strategy for getting drugs into the brain by
attaching them to a dihydronicotinic acid,
hydrophobic 8.92 crosses the blood-brain barrier
oxidation to 8.91 prevents efflux from brain.
83
Mechanism of Acetylcholinesterase
Scheme 8.23
84
Inactivation of Acetylcholinesterase by
Diisopropyl Phosphorofluoridate
Scheme 8.24
affinity labeling agent
irreversible inhibition
Inactivation prevents degradation of the
excitatory neurotransmitter acetylcholine.
Accumulation of acetylcholine causes muscle cells
in airways to contract and secrete mucous, then
muscles become paralyzed.
85
Reactivation of Inactivated Acetylcholinesterase
by Pralidoxime
Scheme 8.25
86
Temporary inhibition of acetylcholinesterase
enhances cholinergic action on skeletal muscle.
Scheme 8.26
covalent, but reversible inhibition
Used for the neuromuscular disease myasthenia
gravis
87
Reversible (noncovalent) inhibitors of
acetylcholinesterase, such as donepezil and
tacrine are used for Alzheimers disease.
Enhances neurotransmission involved in memory.
88
S-Oxidation
Poor oral bioavailability of brefeldin A.
Converted to Michael addition sulfide prodrug
(8.98). S-Oxidation and elimination gives
brefeldin A.
Scheme 8.27
antitumor, antiviral agent
89
Aromatic HydroxylationCyclohexenones as prodrugs
for catechols
Scheme 8.28
aromatic hydroxylation
oxidation next to sp2 carbonyl
90
Alkene Epoxidation
active anticonvulsant agent
91
Transamination
Stimulation of pyruvate dehydrogenase results in
a change of myocardial metabolism from fatty acid
to glucose utilization. Glucose metabolism
requires less O2 consumption. Therefore,
utilization of glucose metabolism would be
beneficial to patients with ischemic heart
disease (arterial blood flow blocked less O2
available).
92
Arylglyoxylic acids (8.104) stimulate pyruvate
dehydrogenase, but have a short duration of
action.
Oxfenicine (8.105, R OH) is actively
transported and is transaminated (a PLP
aminotransferase) in the heart to 8.104 (R OH).
93
Reductive ActivationAzo Reduction
Scheme 8.29
Anaerobic cleavage by bacteria in lower bowel
ulcerative colitis
For inflammatory bowel disease
Causes side effects
94
To prevent side effect by sulfapyridine a
macromolecular delivery system was developed.
poly(vinylamine)
Not absorbed or metabolized in small intestine.
spacer
Released by reduction at the disease site.
Sulfapyridine is not released (still attached to
polymer). More potent than sulfasalazine.
95
Azido Reduction
antiviral drug
Vidarabine is rapidly deaminated by adenosine
deaminase. 8.110, R N3 is not a substrate for
adenosine deaminase and also can cross the
blood-brain barrier for brain infections.
96
Sulfoxide Reduction
anti-arthritis
Sulindac is inactive in vitro the sulfide is
active in vitro and in vivo.
97
Sulindac is an indane isostere of indomethacin,
which was designed as a serotonin analog. The
5-F replaced the 5-OMe group to increase
analgesic properties. The p-SOCH3 group replaced
p-Cl to increase water solubility.
98
Disulfide Reduction
To increase the lipophilicity of thiamin for
absorption into the CNS.
Scheme 8.30
nonenzymatic
poorly absorbed into CNS
99
To diminish toxicity of primaquine and target it
for cells with the malaria parasite, a
macromolecular drug delivery system was designed.
Intracellular thiol much higher than in blood
selective reduction inside the cell
antimalarial, toxic
primaquine
for improved
uptake in liver
Therapeutic index of 8.116 is 12 times higher
than 8.115 in mice.
100
Nitro Reduction
Scheme 8.32
Mechanism-based inactivator of thymidylate
synthase
101
Nucleotide Activation
Scheme 8.33
Anti-leukemia drug
Inhibits several enzymes in the purine nucleotide
biosynthesis pathway.
102
Phosphorylation Activation
2?-deoxyguanosine
antiviral
Resembles structure of 2?-deoxyguanosine
viral thymidine kinase
Uninfected cells do not phosphorylate acyclovir
(selective toxicity)
R PO3
viral guanylate kinase
R P2O63-
viral phosphoglycerate kinase
R P3O94-
103
Acyclovir triphosphate is a substrate for viral
?-DNA polymerase but not for normal ?-DNA
polymerase Incorporation into viral DNA leads to
a dead-end complex (not active). Disrupts viral
replication cycle and destroys the virus. Even if
the triphosphate of acyclovir were released, it
is too polar to be taken up by normal cells. High
selective toxicity
104
Resistance to Acyclovir
Modification of thymidine kinase Change in
substrate specificity for thymidine
kinase Altered viral ?-DNA polymerase
105
Only 15-20 of acyclovir is absorbed Therefore,
prodrugs have been designed to increase oral
absorption.
Hydrolyzes here
Prodrug for a prodrug
adenosine deaminase
acyclovir
106
Hydroxylates here
xanthine oxidase
acyclovir
This prodrug is 18 times more water soluble than
acyclovir.
107
A bipartate carrier-linked prodrug of acyclovir,
the L-valyl ester of acyclovir, has 3-5 fold
higher oral bioavailability with the same safety
profile.
108
An analog of acyclovir whose structure is even
closer to that of 2?-deoxyguanosine is
ganciclovir.
More potent than acyclovir against human
cytomegalovirus.
109
Two carbon isosteres of ganciclovir are available.
C in place of O
C in place of O
Better oral absorption than penciclovir Converted
to penciclovir rapidly
110
Sulfation Activation
Activity of minoxidil requires sulfotransferase-ca
talyzed sulfation to minoxidil sulfate.
hair growth
Inhibitors of the sulfotransferase inhibit the
activity of minoxidil, but not minoxidil sulfate.
111
Decarboxylation Activation
An imbalance in the inhibitory neurotransmitter
dopamine and the excitatory neurotransmitter
acetylcholine produces movement disorders, e.g.
Parkinsons disease. In Parkinsons there is a
loss of dopaminergic neurons and a low dopamine
concentration. Dopamine treatment does not work
because it cannot cross blood-brain barrier, but
there is an active transport system for L-dopa
(levodopa, 8.133, R COOH).
112
After crossing blood-brain barrier
L-aromatic amino acid decarboxylase (PLP)
dopamine (R H)
Does not reverse the disease, only slows
progression.
113
Combination Therapy
Monoamine oxidase B (MAO B) degrades dopamine in
the brain. Therefore, a MAO B-selective
inactivator is used to protect the dopamine -
selegiline (L-deprenyl). Peripheral L-aromatic
amino acid decarboxylase destroys gt95 of the
L-dopa in the first pass. Maybe only 1 actually
gets into brain.
114
To protect L-dopa from peripheral (but not CNS)
degradation, inhibit peripheral L-aromatic amino
acid decarboxylase with a charged molecule that
does not cross the blood-brain barrier.
(used in U.S.)
(used in Europe and Canada)
Selectively inhibits peripheral L-amino acid
decarboxylase. The dose of L-dopa can be reduced
by 75.
115
Selective Inactivation of Brain Monoamine Oxidase
A
Earlier we found that inactivation of brain MAO A
has an antidepressant effect, but a
cardiovascular side effect occurs from
inactivation of peripheral MAO A.
8.136 (R COOH) is actively transported into the
brain, where L-aromatic amino acid decarboxylase
converts it to 8.136 (R H), a selective MAO A
mechanism-based inactivator. Carbidopa protects
8.136 (R COOH) from decarboxylation outside of
the brain.
116
Selective Delivery of Dopamine to Kidneys
Dopamine increases renal blood flow. Prodrugs
were designed for selective renal vasodilation.
Scheme 8.34
L-dopa
L-?-glutamyl-L-dopa
Dopamine accumulates in the kidneys because of
high concentrations of L-?-glutamyltranspeptidase
and L-aromatic amino acid decarboxylase there.
Example of a carrier-linked prodrug of a
bioprecursor prodrug for dopamine.