EX2 Alpha Antagonists (MC)

Non-Selective a-Antagonists (α1 and α2)

Imidazoline derivatives

Non-selectivity for either a-receptor sub-type arises because the aromatic ring does not have an ortho substituent (allows free rotation of the aromatic ring).

Phentolamine: the imidazoline ring is connected to the phenyl ring via a nitrogen

• Peripherally, phentolamine prevents vasoconstriction.

• Important Structural Features:

B-chloroethylamine derivative

From a structural perspective, what makes phenoxybenzamine an irreversible antagonist?

formation of azirdinium → covalent bond formation

From a structural perspective, why is phenoxybenzamine non-selective?

no imidazoline, no ortho substituents, no shape

Drop a pin on reactive fg and fg that makes it irreversible

reactive shown

Covalent bond irreversible

Selective α1 Antagonists

Block peripheral vasoconstriction by NE; results in decreased peripheral resistance and a fall in BP.

Quinazolines (peripheral antihypertensives) and the duration of action

Alfuzosin

Used in BPH

Piperazine ring at the 3-position replaced by diamino containing chain at the 3-position

instead of the piperazine.

• Chain terminates with an amide attached to tetrahydrofuran

What is the role of the steric bulk of the substituent as it relates to pharmacokinetics?

Increases protection of the amide against amide hydrolysis

also increases duration of action

Selective α1A Antagonists (only will see A, not B or C) chemical class

phenethylamine for BPH

Phenethylamine SAR

phenethylamine

target

action

Target for Drug Action: a1 receptor

Action at Target: Antagonist

Selective α2-Antagonists

Enhances NE release by blocking presynaptic receptor

• Blocking the presynaptic receptor causes increased neurotransmitter biosynthesis,

increased neurotransmitter release, and decreased uptake of NE.

• This results in increased NE neurotransmission. Used as an antidepressant

Selective α2-Antagonists structure