MEDICINAL CHEMISTRY OF SYMPATHOLITICS

two ___________________ prevent MAO metabolism

alpha methyl groups from the Nitrogen

What type of binding interactions occur between the OH group on a drug and the b2 receptor?

hydrogen bonding

The complimentary binding groups on the b2 receptor are Ser hydroxyl side chains. The drug may be a hydrogen bond donor, or a hydrogen bond acceptor for binding interactions with the b2 receptor to activate the G-protein for appropriate 2nd messenger responses.

What portion of the NE life cycle does a tyrosine hydroxylase inhibitor interfere with

biosynthesis

Tyrosine hydroxylase is a biosynthetic enzyme in the catecholamine cascade.

converting a zwitterionic amino acids to an ester salt dramatically increases ___________________________

water solubility.

basic secondary amine pKa __________________ and percent ionization at physiological pH

between 8-10

~99% ionization at physiological pH

hypotensive side effects can be produced by ____________________ antagonism

α-receptor

ISA (intrinsic sympathomimetic activity) occurs when a _____________________ is in the meta, or para position of the aromatic ring from the oxypropanolamine side chain of β-antagonists

hydrogen bond donor

Biosynthesis of NE

L-Tyrosine + Tyrosine Hydroxylase = L-DOPA (DiOxyPhenylAlanine)

DOPA + L-Aromatic Amino Acid Decarboxylase = Dopamine

Dopamine + Beta-hydroxylase = Norepinephrine.

Metyrosine

Tyrosine hydroxylase inhibitor

- methyl group in alpha position

α-methylnorepinephrine

presynaptic α2 agonist

- DEC NE release

release of NE

classical exocytosis (Calcium Flux)

Reserpine Function

Decrease NE Storage - Block vesicular storage

- Inhibits 5-HT (Seretonin), NE, DA storage

*Also interfering with Serotonin —> unintended consequence

--> No long term use

Guanethidine Sulfate (Ismelin) Function

Decrease NE release - Disrupt exocytosis

Guanadrel Sulfate (Hylorel) Function

Decrease NE release - Disrupt exocytosis

amphetamine Drug Class & Function

indirect α-agonists

- Promote NE release - Enhance exocytosis and/or release

pseudoephedrine

mixed α-agonists

- Promote NE release - Enhance exocytosis and/or release

concern with enhancing exocytosis

May enhance exocytosis so much that you deplete everything stored, which stops your intended results

Reserpine halts ____________________

Vesicular storage

- Reserpine blocks the pathway because it is too big to be transported

Vesicular Storage NE

H+ transport primes the vesicular transporter

nH+ are exchanged for NE

NE is transported into the vesicle from the cytoplasm

Which enantiomer is most likely to interact with the receptor

R (-) Enantiomer

- hydroxyl oriented toward binding site

all α and β receptors are members of the _____________________ family

G-protein coupled receptor (GPCR)

α2 receptor amines

Asp in critical position (transmembrane region 3)

Ser (transmembrane region 5)

Cys (three aa away from Ser)

β2 receptor amines

Asp in critical position (transmembrane region 3)

Ser (transmembrane region 5)

Ser (three aa away from Ser)

- Ser bind to catechol

Ligand Binding Agonists

Activate (Mimic Neurotransmitter)

Ligand Binding Antagonists

Prevent Neurotransmitter Activation of target tissue

- Usually bigger than endogenous neurotransmitters

- Keep it there long enough to overcome endogenous ligand

Monoamines (NE + DA) are dependent on ______________ to be stored inside vesicles

anti-port exchange of protons (positively charged proton for a positively charged monoamine)

- protons are highly concentrated inside the vesicle (low pH)

- as the amines are produced in the cytoplasm, it will be exchanged for protons to concentrate the monoamine against the concentration gradient to concentrate it inside the vesicle

______________ decrease NE release & disrupt exocytosis

gaunadines

all α and β receptors differ based on

- composition of aa

- length of loop

- length of amine and carboxy terminus

catechol functional group binds to transmembrane region __________

5

α1 second messenger system

coupled to Gq and Gca

- found on blood vessels

- vasoconstriction of smooth muscle when calcium is released

α2 presynaptic second messenger system

coupled to Gi

α2 postsynaptic, platelets second messenger system

coupled to Gca

β second messenger system

coupled to Gs

- stimulating production of cAMP

- Cardiac Muscle: Contracts

- Smooth Muscle (Lungs & Blood Vessels): Relax

Full α1 agonists

activate BOTH Gq and Gca

Partial α1 agonists

activates only 1 G protein (Gq OR Gca), maybe not even fully

MAO is followed by ____________________

aldehyde reductase

OR

aldehyde dehydrogenase

aldehyde reductase

transforms into alcohol

aldehyde dehydrogenase

oxidize up to carboxylic acid

Monoamine Oxidase A Isoform Substrate

NE, E, Seretonin

Monoamine Oxidase B Isoform Substrate

Dopamine

COMT

phase 2 enzyme

- adds on methyl group (preferred to add to meta hydroxyl)

terminating NE

1. Metabolism: COMT + MAO

2. Reuptake: Remove neurotransmitter from synapse

Reuptake of NE

High affinity presynaptic reuptake transporters

- takes neurotransmitter back into the presynaptic neuron (in the cytoplasm)

- it is then stored in the vesicles & recycled (reused)

Low affinity reuptake transporters used at high NE concentrations

Low affinity reuptake transporters must have

high neurotransmitter concentration

reuptake transporters priming mechanism

Na+/Cl- dependent: Takes 1-3 Na as well as a Cl to prime the synaptic neurotransporter to move the neurotransmitter

- high sodium concentration in extracellular fluid

cocaine drug class

indirect sympathomimetic

- blocks reuptake

BP INC

monoamines

dopamine, norepinephrine, serotonin

SAR

structure activity relationship

α-Adrenergic Agonist SAR

1. phenylethylamine (prototype)

2. β-hydroxyl group (R-configuration)

3. ArOH

4. 2,5 dimethoxy substitution can provide intrinsic activity

5. N-substitution is small, H or CH3 --> larger group leads to Beta affinity

6. α-substitution is H or CH3 --> larger group leads to Beta affinity

α-Adrenergic Agonist prototype

phenylethylamine

intrinsic activity

refers to the ability of a drug to activate a receptor upon binding

nasal or injection by passes

first pass effects

When a drug's pKa is close to the physiological pH (around 7.4), the drug will be mostly _____________ in the body

ionized

low dose of dopamine causes

DA Agonist --> stimulates dopamine receptors

- vasodilation (INC blood flow in kidneys)

moderate dose of dopamine causes

Beta Agonist

- INC HR

high dose of dopamine causes

Alpha Agonists

low doses of dopamine can be used in shock to ensure the ___________ do not shut down

kidneys

Direct acting α-Adrenergic Agonist

Norepinephrine

Epinephrine

Phenylephrine

metaraminol

methylsynephrine

methoxamine

midrodrine

catecholimines are

Direct acting α-Adrenergic Agonist

phenylephrine drug class

Direct acting α-Adrenergic Agonist

- NOT a good vasoconstrictor orally

phenylephrine DOA

good DOA due to no COMT

alpha-CH3 slows

MAO metabolism

Direct acting α-Adrenergic Agonist uses

vasoconstrictor

mixed alpha agonists SAR

missing two hydroxyl groups

mixed alpha agonists

ephedrine

pseudophedrine

phenylpropanolamine

indirect alpha agonists SAR

minus 3 hydroxyl groups

indirect alpha agonists

lisdexamfetamine

mephentermine

imidazoline

partial alpha-1 agonist

forming the ester salt of an amine drug makes the drug more

soluble

amino acids are ______________

zwitterions

how to form the salt of an amine

adding HCl to the amine and making the carboxylic acid into an ester (CO2CH2CH3)

Methyldopa / Methyldopate HCl

Central Antihypertensive

droxidopa

prodrug that undergoes decarboxylation to form norepinephrine

- Peripheral vasoconstrictor for neurogenic orthostatic hypotension (not distributed to the CNS due to the beta-hydroxyl)

α2-agonists SAR

1. basic functional group (imidazoline ring or fragmented mimic)

2. chain conjugating electron flow to aromatic ring

3. ortho EWG

α2-agonists prototype

Clonidine

α2-agonists drugs

Clonidine

Guanabenz

Guafacine

EWG such as Cl will allow the drug to be more

lipophilic --> crosses BBB