4/5 - MedChem Adrenergic Nervous System Flashcards
a-Methyltyrosine
TARGET?
(Metyrosine, Demser®)
- *Competitive INHIBITOR** of
- *L-Tyrosine Hydroxylase**
Rate-limiting enzyme that converts:
L-Tyrosine –/–> L-Dopa (CATECHOL)
VVV
Inhibits production of NOREPINEPHRINE
Aldomet
TARGET?
PRODRUG = a-Methyldopa
- *Competitive inhibitor** that targets:
- *L-Aromatic AA Decarboxylase**
Non-selective enzyme that converts:
L-Dopa –/–> Dopamine
VVV
Ultimately inhibits Biosynth of NorEpinephrine
- *Carbidopa + L-Dopa**
- *SINEMET**
TARGET?
PARKINSONS DRUG
Carbidopa is a true inhibitor of:
L-Aromatic AA Decarboxylase
Converts:
- *L-Dopa –/–> Dopamine**
- inhibits production of NE*
- *Carbidopa** reduces L-dopa conversion to Dopamine in BLOOD
- *L-Dopa** –> allows for it cross BBB, active transporters for AA’s in brain
- ↑*Dopamine in BRAIN
Disulfram / Nepicastat
TARGET?
PTSD + Cocaine Dependence
Inhibitor of:
DBH = Dopamine B-Hydroxylase
Converts:
Dopamine –/–> NorEpinephrine
uses:
Vitamin C Oxidation
- *PNMT**
- *Phenylethanolamine N-Methyl Transferase**
Function / Cofactor?
PNMT + SAM (cofactor) converts:
NE –> Epinephrine
Occurs @Adrenal Glands
Tetrahydrofolate adds C1 groups
VMA
Vanillyl Mandelic Acid
Major NE/Dopamine metabolite in:
PNS
from aldehyde dehydrogenase
can eventually degrade down to MHPG
MHPG
Major NE / Dopamine metabolite in:
CNS
main endpoint
from alcohol dehydrogenase
- *COMT**
- *Function / Location**
@Adrenergic / Dopaminergic NERVE TERMINALS
to
degrade NT’s (NE + Dopamine) –> target CATECHOL
@Liver & Kidney
at a higher concentration to detoxify CATECHOL METABOLITES
b4 they are further oxidized to TOXIC O-QUINONES
–> alkylate proteins / neurons
Entacapone / Tolcapone
Target / Use
COMT INHIBITORS
Adjuncts to L-Dopa –> PARKINSON
(like Carbidoma in Sinemet)
Entacapone = PERIPHERAL acting drug
PREFERRED, since it does NOT increase chance of QUINONE in Brain
Tolcapone = more LIPOPHYLIC –> can cross BBB
can cause LIVER DMG / quinones
Name of Enzymes for each Reaction?
1) L-Tyrosine Hydroxylase
L-Tyrosine –> L-Dopa
2) L-Aromatic AA Decarboxylase
L-DOPA -> Dopamine
3) Dopamine B-Hydroxylase
Dopamine –> NE
- *Drugs acting on Catecholamine Uptake**
- *ReUptake via NorEpinephrine Transporter 1**
Cocaine + TriCyclic Antidepressants (Desipiramine)
Potentiate sympathetic effects by inhibiting NE uptake by sympathetic nerves
Drugs acting on Catecholamine Storage & Release
Repackaging by VMAT
Vesicular Monoamine Transporter
- *Reserpine**
- *depletes NE** from its storage vesicles by blocking VMAT
- *Guanethidine + Guanadrel**
- *replace NE** in the vesicle then limits release
- can NOT cross BBB due to BASIC GUANIDINE moiety*
a-Adrenergic Receptor Agonists
(Phenylethanolamine Derivatives)
important SAR conclusions
- *a-1 agonist** can bind
- *WITHOUT a CATECHOL**
a-1 agonist
canNOT take a Methyl group @ Alpha Position
VVV
but this forms an:
additional methyl binding pocket –> tighter a-2 receptor binding
Midodrine
Target?
a-1 Adrenergic Agonist
prodrug of methoxamine analogue
rapid activation by liver amidases –> active metabolite
Midodrine a1 selectivity >> Methoxamine
Methoxamine has an Alpha-Alkyl group
which is not good for a1 selectivity
Tetrahydrozoline + Naphazoline
Visin / Privine
Targets?
a1-Adrenergic Receptor Agonists
Imidazoline Derivatives
TOPICAL
Nasal Decongestant&Eye Drops
possess 1-o-substitution on aromatic ring
connected via 1 or 2 atoms to imidazoline ring
- *Clonidine**
- *(**+ other -nidines)
Target?
Guafacine / Guanabenz / Brimonidine / Apraclonidine
Selective a2-Agonists
steric crowding by the 2 bulky o-substituents
does NOT permit the coplanar conformation of
aryl ring & imidazole ring
which is needed for selective a2 agonist binding to a2 adrenergic receptors
- *Chlorines = EWG’s** –> adjust pH so it can CROSS BBB
- so guanidine group is NOT charged*
Oxymetazoline + Xylometazoline
Target?
MIXED a-Agonist
a-1 agonist + a-2 partial agonist
topical decongestants
bulky tertiary butyl group @ para position
VVV
diminishes affinity to the a2 adrenergic receptors
What SAR diminishes a-2 activity?
Bulky Tertiary Butyl Group
@
Para-Position
diminishes affinity for a2 adrenergic receptors
Phenoxybenzamine
Dibenzyline
Target?
- *a-adrenergic receptor ANTAGONIST**
- *IRREVERSIBLE ANATAGONIST**
alkylates the a-adrenergic receptors via its
reactive aziridine intermediate
Phentolamine + Tolazoline
Imidazoline-Type
Target?
NON-SPECIFIC a-adrenergic ANTAGONIST
potent but non-specific
Tolazline lacks ortho-substitition
which is needed for a-agonist activity:
1 substituent = a1 agonist
2 subs (catechol) = a2 agonist
Quinazolines = -zosins
Prazosin / Doxazosin
Terazosin / Trimazosin
Target?
SELECTIVE a-1 ANTAGONIST
Contain a 4-amino-6,7-dimethoxyquinazoline ring system attached to a piperazine nitrogen
PK properties depend on the R-GROUP
Afluzosin
Target?
UROSELECTIVE a-1 ANTAGONIST
for
- *BPH**
- short half life –> extended release dosage form
- non-specific,** but functionally uroselective
Tamsolosin + Silodosin
Phenylethanolamines
Uroselective a1 Antagonist
a-1 receptor Antagonist for BPH
Yohimbine + Rauwolfscine
target?
Selective a2 Antagonist
alkaloids from bark/roots
not FDA approved, but used for:
Aphrodisiac + Bodybuilder for fat loss
What SAR gives
B2 Selectivity?
Bulky Substituent = Tert-butyl
@
Nitrogen
&
No Catechol / Catechol substitution = B2 Selectivity
Dobutamine
Target
B-1 Adrenergic Agonist
for Cardiac STIMULATION + CHF Failure
Dobutamine is a dopamine analogue with:
Chiral & Bulky N-substituent
S-isomer = a1 agonist // R-isomer = a1 antagonist –> CANCEL OUT
-TEROL’s
Salmeterol / Albuterol / Pirbuterol / Fomoterol
Target?
b2-Adrenergic agonists
with a modified m-OH –> allows for HYDROGEN BONDING
VVV
prevents ANTAGONIST function
Formoterol = longest acting
due to longer degradation, meta-group on phenyl ring @ end
MetaProterenol / Fenoterol / Bambuterol
Target?
SELECTIVE B2 Agonist
- *Isoproterenol** is made selective by:
- *moving 4-OH –> 5-OH**
Isoetharine + Ritodrine (yutopar)
SELECTIVE B2 Agonist
- *isoproterenol** can ALSO be made selective by:
- *Adding a Small Alkyl group on Alpha-Carbon**
Ritodrine –> used to control premature labor
Catecbol is sitll present –> COMT degradation (fast)
**What SAR modification makes a _B2 Agonist (isoproterenol) --\> SELECTIVE?_**
moving 4-OH –> 5-OH
Metaproterenol / Bambuterol / Fenoterol
Adding Small Alkyl Group (Ethyl) on a-carbon
Isoetharine / Ritodrine
Early -olol’s
Propranolol / Nadalol / Timolol / Nadolol
Target
Non-Selective B-Adrenergic ANTAGONIST
Catechol –> Chlorine
served as lead compound to create Antagonist
Elongation of Ethylamine by
OXYMETHYLENE bridge + C1 placement
VVV
Propranolol
Para Substituated -olol’s
Metoprolol / Atenelol / Bisoprolol
- *SELECTIVE B1- Antagonist**
- *PARA SUBSTITUENT**
- B2 prefers there to be NOTHING @ Para position*
Psudoephedrine / Amphetamine / Ecstasy
Target?
- *INDIRECT-acting Adrenergic Agonist**
- *Increase NE concentration @ receptor**
- not selective*
CH3 (2 positions from nitrogen) –> prevent MOA degradation
No Catechol –> no COMT degradation
- *Amphatamine**
- *CNS stimulant**, stimulates NE / 5-HT / DA release in brain
Tyramine
Patients taking
MAO-Inhibitors / indirect acting adrenergic agonist
should
Avoid taking TYRAMINE
High Tyramine –> displace/release NE + Epinephrine
VV
hypertensive crisis
