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Chapter 6: Drugs Acting on Autonomic Nervous System: Adrenergic Agonists and Antagonists Agents Back To Chapter

6.8: Adrenergic Agonists: Chemistry and Structure-Activity Relationship

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Adrenergic Agonists: Chemistry and Structure-Activity Relationship

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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.

–CH₃substitution 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.

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Adrenergic Agonists Chemistry Structure-activity Relationship SAR Phenylethylamine Moiety Aromatic Ring Ethylamine Side Chain Catecholamines Epinephrine Adrenoceptors Hydrogen Bonding Norepinephrine Amino Group Alpha And Beta Carbon Potency Selectivity Duration Of Action Optical Isomerism Levorotatory Dextrorotatory Receptor Affinity

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