6.8:
Adrenergic Agonists: Chemistry and Structure-Activity Relationship
Structurally, adrenergic agonists are characterized by a fundamental β-phenylethylamine skeleton.
For maximum agonist activity, –OH groups at positions 3 and 4 of the aromatic ring are essential. The absence of one or both –OH groups diminishes potency while enhancing metabolic stability and CNS penetration.
The inclusion of a two-carbon linker between the ring and amino group is essential for optimum agonist activity.
Bulkier alkyl substituents on the amino group generally enhance β but decrease α-agonist activity, with α-selective phenylephrine being an exception.
–CH3 substitution on the α-carbon improves lipophilicity, reduces metabolic susceptibility to MAO, and extends the duration of action.
Conversely, –OH substitution on the β-carbon lowers lipophilicity and CNS penetration but enhances both α- and β-agonist activity.
In conclusion, structural modifications of the β-phenylethylamine skeleton yield agonists with varying adrenoceptor affinities, distinct pharmacokinetic profiles, and differing bioavailability.
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.