6.8 : Adrenergic Agonists: Chemistry and Structure-Activity Relationship

Adrenergic agonists' structure-activity relationship (SAR) determines their selectivity and efficacy. These agonists comprise a phenylethylamine moiety with an aromatic ring and an ethylamine side chain.

Aromatic ring substitutions: Substituting the aromatic ring with –OH groups at positions 3 and 4 yields catecholamines (e.g., epinephrine), which have a high affinity for adrenoceptors. Hydrogen bonding between –OH groups and receptors enhances adrenergic activity.

Separation of the aromatic ring and amino group: A two-carbon chain optimally separates the amino group from the ring, as seen in norepinephrine and epinephrine.

Substitutions on the amino, α, and β-carbon: Modifications on the amino group and α-carbon affect potency, selectivity, and duration of action. α-methyl substitution increases α₁-receptor selectivity. Substituting the amino group with a bulkier alkyl group increases β₂-selectivity.

Optical Isomerism: Optical isomers of adrenergic agonists have different pharmacological properties. Levorotatory β-hydroxyl and dextrorotatory α-methyl substitutions exhibit maximum agonist potency.

Understanding the SAR of adrenergic agonists is crucial for developing targeted and effective medications with specific receptor affinity and selectivity.