2.4.1 Med Chem Beta-blockers

Adrenergic receptor targeting for antihypertension includes blocking __________ and __________ receptors and agonizing __________ and __________ receptors.

α1; β1; α2; β2

First‑generation beta blockers are __________ and block both β1 and β2.

Nonselective

Second‑generation beta blockers are relatively __________ for β1 over β2.

Selective

Third‑generation beta blockers combine __________ antagonism with β blockade.

α1

Replacing catechol hydroxyls in isoproterenol with chlorines yielded dichloroisoproterenol, converting a β agonist into a β __________.

Antagonist

Inserting -OCH2- between the aromatic ring and ethanolamine of pronethalol produced __________, the first clinically successful β blocker.

Propranolol

Nonselective β antagonists are commonly aryloxy‑propanolamines featuring a two‑ring aryl system and a lipophilic __________ group.

N‑substituent

Greater lipophilicity yields higher CNS penetration and primary __________ clearance, whereas more hydrophilic agents are cleared renally.

Hepatic

Some nonselective β blockers show membrane‑stabilizing or intrinsic sympathomimetic activity, with __________ exhibiting membrane stabilization at high dose.

Propranolol

Para‑substitution on the phenyl ring of aryloxy‑propanolamines imparts selectivity for __________ receptors.

β1

Esmolol has a very short half‑life (~9 minutes) due to rapid __________ hydrolysis.

Ester

Nebivolol is highly β1 selective at low doses and also enhances endothelial __________ synthesis for vasodilation.

NO

Carvedilol is 10-100‑fold more potent as a β blocker than as an α1 blocker, whereas labetalol is about __________‑fold more potent as a β blocker than an α1 blocker.

1

General SAR: N‑isopropyl or t‑butyl groups impart β over α selectivity, while an __________ N‑arylalkyl group permits α1 interaction.

Arylalkyl

Most β blockers undergo oxidative metabolism via __________, with atenolol and nadolol exceptions cleared renally.

CYP2D6

α1 antagonists are substituted quinazolines with an acylated piperazine ring, and reduction of a __________ to tetrahydrofuran increases duration for terazosin.

Furan

Selective α1A antagonists such as alfuzosin, tamsulosin, and silodosin treat benign __________ hyperplasia by blocking prostatic smooth muscle α1A.

Prostatic

Centrally acting α2 agonists (clonidine, guanfacine) penetrate the CNS to reduce sympathetic output, while __________ is a prodrug converted to α‑methylnorepinephrine for use in pregnancy.

Methyldopa