Lecture 12 - Alpha Receptor Antagonists

Non-Selective alpha-Antagonists (α1 and α2) list

imidazoline derivatives (phentolamine), beta-chloroethylamine derivative

Imidazoline derivatives SAR

1. 2 aromatic rings – increased bulk, decreased intrinsic activity (promotes antagonism)

2. No “ortho” substituents on the Ar rings (allows for free rotation of the aromatic rings). Results in loss of α selectivity and increased antagonist action

3. carbon and nitrogen bridging members also contribute to non-selectivity

beta-chloroethylamine derivative

phenoxybenzamine hydrochloride

beta-chloroethylamine derivative SAR

irreversible alpha-antagonist by forming a covalent bond with a receptor nucleophile (due to nucleophile N and electrophile mechanism that sucks), causes aziridinium formation

Selective α1 Antagonists list

Quinazolines (peripheral antihypertensives), Alfuzosin

Quinazolines (peripheral antihypertensives) SAR

• piperazine attached to amide (susceptible to amide hydrolysis)

• Increased steric bulk (addition of flat with bulk) protects the terminal amide group from hydrolysis and may contribute to increased half-life and duration of action

• Structural differences arise from the nature of the aryl group attached to the amide carbonyl

Quinazolines from shortest to longest acting

prazosin → terazosin → doxazosin

Alfuzosin special SAR (from quinazolines)

• Piperazine ring at the 3-position replaced by diamino containing chain at the 3-position instead of the piperazine.

Selective alpha-1A Antagonists

Phenethylamines

Phenethylamines SAR

• Phenethylamine present

• Aralkyl-like substituent on the basic nitrogen (α-antagonism)

• Methyl group on the α-carbon atom (increases α1-receptor selectivity)

• Polar groups (amide, sulfonamide, phenol, amino) on the aromatic ring

MOA of mirtazepine

1. Enhances NE release by blocking presynaptic receptor (due to insane bulk)

2. Blocking the presynaptic receptor causes increased neurotransmitter biosynthesis, increased neurotransmitter release, and decreased uptake of NE.

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

target for drug action of quinazolines

a1 receptors in peripheral vasculature

target of drug action of selective alpha 2 antagonists

PRESYNAPTIC alpha 2 receptors

selective alpha 2 antagonists SAR

1. still phenethylamine present

2. ionizable amine

3. lots of ring system bulk that’s clustered together (tries to make smaller to fit into presynaptic receptor)