Untitled Quiz

Sympathomimetic Agents

• Sympathomimetic agents mimic the effects of the sympathetic nervous system
• Classified by their mechanism of action: direct, indirect, or mixed
• Direct-acting agents bind directly to adrenergic receptors
• Indirect-acting agents cause the release of norepinephrine (NE) from nerve terminals, stimulating receptors
• Mixed-acting agents act both directly on adrenergic receptors and indirectly by releasing NE

Direct-Acting Sympathomimetics

• Structure-activity relationships are significant
• Many adrenergic drugs are based on the structure of β-phenylethylamine
• Substitutions on the aromatic ring, amino group, and ethylamine side chain affect receptor selectivity, absorption, metabolism, and duration of action
• Maximal activity of direct-acting sympathomimetic amines occurs in specific configurations

Optical Isomerism

• Stereoselectivity is critical for adrenergic agonist interactions with receptors
• Substitution on carbon 1 or 2 creates optical isomers
• The (1R,2S) isomer often has high direct-acting activity
• (1R) configuration is typically more potent

Separation of Aromatic Ring and Amino Group

• Greatest adrenergic activity occurs when the aromatic ring and amino group are separated by two carbon atoms
• This rule generally applies across different types of activities

R1 Substitution on the Amino Nitrogen

• The amine is ionized at physiological pH, crucial for direct agonist activity
• Replacing nitrogen with carbon significantly reduces activity
• The number of substituents on the nitrogen impacts activity
• Primary and secondary amines show good activity, while tertiary and quaternary ammonium salts do not

Nature of the Amino Substituent

• Amino substituent size affects receptor selectivity and subtype preference
• Larger substituents generally decrease α-receptor activity and increase β-receptor activity
• N-tert-butyl group enhances β2-selectivity

Length of Alkyl Chain

• Increasing the length of the alkyl chain does not improve activity
• Adding a polar functional group like a phenol group at the end of an alkyl chain significantly boosts activity

R2 Substitution on the α-Carbon

• Substituting with small alkyl groups can slow metabolism by monoamine oxidase (MAO) but does not greatly affect duration of action
• Resistance to MAO is more important for noncatechol indirect-acting agents like ephedrine and amphetamine

OH Substitution on the β-Carbon

• Decreases central nervous system (CNS) activity due to reduced lipid solubility
• Enhances activity at both α- and β-receptors
• Example: Ephedrine is less potent than methamphetamine as a stimulant, but more potent in dilating bronchioles and increasing blood pressure and heart rate

Methyl or Ethyl Substitution on the α-Carbon

• Reduces direct agonist activity at both α- and β-receptors
• Ethyl substitution decreases α-activity more than β-activity, producing more β-selective compounds like ethylnorepinephrine and isoetharine

Substitution on the Aromatic Ring

• Maximal α- and β-activity depends on the presence of 3' and 4' hydroxyl groups, which facilitate hydrogen bonding with receptors
• Tyramine, lacking these hydroxyl groups, has no affinity for adrenoceptors
• Catechol moiety can be substituted for other groups to produce selective adrenergic agonists (e.g., replacement of the catechol function of isoproterenol with resorcinol to produce metaproterenol)
• Catechol-containing compounds generally have better absorption characteristics and longer duration of action (DOA)