EX2 Beta Antagonists (MC)

Development of the B-Adrenergic Antagonists

Aryloxypropanolamines (phenyl also works) SAR

Structure Activity Relationships

• Aryloxypropanolamine; NO substituent para to the oxygen on the aryl ring (B1=B2)

• Large branched alkyl group on the basic nitrogen (isopropyl or t-butyl)

• Basic nitrogen is required for binding; ionized form binds to receptor

• NO H-bond donor/acceptors directly attached to the aryl ring (except pindolol and carteolol) (no catechol, no catechol mimics)

Aryloxypropanolamines examples

Non-selective B antagonists with Intrinsic Sympathomimetic Activity (ISA)

Look for an H-bond donor/acceptor N-H group directly attached to the aromatic ring

If there is less ISA, then what kind of agonist do you expect these drugs to be?

partial agonists

B1-Selective Antagonists (Cardioselective) SAR

• Aryloxypropanolamine; with lipophilic substituent para to the oxygen on the aryl ring. The nature of this para substituent also dictates the relative duration of the drug.

• Large branched alkyl group on the basic nitrogen (e.g., isopropyl)

• Basic nitrogen is required for binding; ionized form binds to receptor

• NO H-bond donor/acceptors directly attached to the aryl ring (except acebutolol) - (1 less point of interaction between drug + target, do not get activation)

Aryloxypropanolamines: B1-Selective (cardioselective) antagonists

Combination a and b Antagonists Labetalol and Carvedilol

Target for Drug Action: a and b receptors

Action at Target: Antagonist

Alpha antagonism: decreases peripheral resistance

Beta antagonism: decreases rate and force of heart contraction

Combined effect is an effective control of BP

Important Structural Features - Labetalol

Phenethanolamine N-aralkyl group gives a1-

antagonism