EX2 Alpha Agonists (MC)

Tyrosine hydroxylase catalyzes the

rate limiting (slowest) step in the biosynthesis of NE and DA

What is the key difference between tyrosine and metyrosine? What is the effect of adding this additional group?

adding an alpha methyl group inhibits tyrosine hydroxylase

What is an alternate substrate?

a drug that acts like the substrate but does not produce a biologically relevant product

in the presence of methyldopa, what happens to the conversion of DOPA to dopamine?

decrease in the rate of conversion → less produced over time

a1 receptor

postsynaptic, mediates smooth muscle contraction

subtypes a, b, d

a2 receptor

presynaptic in CNS, postsynaptic in periphery

regulates release and biosynthesis of NE

increases uptake of NE into presynaptic neuron

alpha1 agonist uses

management of shock

decongestant

vasoconstriction

alpha2 agonist uses

HTN

Glaucoma

Spasticity

a1 antagonists

HTN
BPH

a2 antagonists

mild depression (CNS)

How does neurotransmission differ if its primary post synaptic vs pre synaptic?

presynaptic → decreased NE neurotransmission

postsynaptic → increased NE neurotransmission

two chemical classes of alpha agonists

phenethanolamines and 2-aryl imidazolines

phenethanolamines SAR

alpha agonist

phenethanolamine derivatives

Which OH configuration increases receptor affinity?

R

Which functional group imparts a1 selectivity at the a carbon?

CH3

2-aryl imidazolines SAR

direct acting a1 agonists

which structural features are responsible for selective a1 receptor agonist activity?

ortho alkyl groups on aromatic ring

2-aryl imidazoline derivatives

Indirect acting a1 agonists

promotes release of NE from synaptic vesicles

NOTE absence of OH groups

targets presynaptic storage vesicles

Mechanism of action for indirect a1 agonists (story problem)

1. enters presynaptic neuron (active transport)

2. Disrupts storage vesicle

3. Causes NE release (into synapse, increases NE neurotransmission)

Mixed acting a1 agonists (direct and indirect)

Phenethylamine/Phenethanolamine derivatives

These agents have a direct effect at the post-synaptic a1-receptor and have an indirect effect

Presence of one OH group imparts some direct activity at the receptor

Which functional group is responsible for the direct effect of psuedoephedrine?

B OH

If a drug has a direct effect at the post-synaptic a1-receptor, then what should you observe?

binding +activation of receptor

a2 adrenergic receptors

decreased release and biosynthesis of NE

Increased uptake of NE into presynaptic neuron

2-amino imidazoline SAR

Agents are used as centrally acting antihypertensives

which form binds to receptors

IONIZED FORM

Which form of clonidine binds to receptor?

ionized form

Imidazoline absent on a2 agonists