Strutre-Activity Relationship
 The relationship between the chemical structure of a molecule and its biological activity.
 This idea was first presented by Crum-Brown and Fraser in 1865.
SAR of Adrenergic Drugs
Separation of aromatic ring and amino group
 The greatest adrenergic activity occurs when two carbon atoms separate the aromatic ring from the amino group.
Substitution at R1 (alpha & beta selectivity)
 R1 substituion on amine group(N), increase in the size of R1 leads to increase in beta activity and decrease in alpha activity.
 Tertiary butyl substitution on amine group, increases beta 2 selectivity.
 Degradation by Monamine oxidase (MAO) is decreased on R1 substitution.
Substitution at Carbon 1 (OH)
 OH group substitution on the C1 generally decreases CNS activity largely because it lowers lipid solubility.
 However, such substitution greatly enhances agonist activity at both alpha and beta receptors.
Substitution at R2 on Carbon 2
 Substitution by small alkyl groups (methyl, ethyl) leads to decrease in degradation by Monamine oxidase (MAO). But those drugs are still substrates for COMT and this may affect duration of action of drug, a little.
 Specifically on ethyl group substitution, drug become more beta selective. Also CNS activity, oral activity and duration of action is increased.
Substitution on aromatic ring
 4'-OH is important for beta activity.
 3'-OH is important for alpha activity.
 Optimal activity on 3',4'-diOH : Both alpha and beta agonist activity. But easily metabolized by catechol-o-methyl transferase (COMT) thus oral activity is poor and short duration of action. Drug become hydrophilic which leads to poor CNS activity.
 3'-5'-diOH and 3'-CH2OH,4'-OH : Beta 2 selectivity is increased. Degradation by catechol-o-methyl transferase (COMT) is decreased thus drug absorption, oral activity and duration of action are increased.
 The relationship between the chemical structure of a molecule and its biological activity.
 This idea was first presented by Crum-Brown and Fraser in 1865.
SAR of Adrenergic Drugs
Separation of aromatic ring and amino group
 The greatest adrenergic activity occurs when two carbon atoms separate the aromatic ring from the amino group.
Substitution at R1 (alpha & beta selectivity)
 R1 substituion on amine group(N), increase in the size of R1 leads to increase in beta activity and decrease in alpha activity.
 Tertiary butyl substitution on amine group, increases beta 2 selectivity.
 Degradation by Monamine oxidase (MAO) is decreased on R1 substitution.
Substitution at Carbon 1 (OH)
 OH group substitution on the C1 generally decreases CNS activity largely because it lowers lipid solubility.
 However, such substitution greatly enhances agonist activity at both alpha and beta receptors.
Substitution at R2 on Carbon 2
 Substitution by small alkyl groups (methyl, ethyl) leads to decrease in degradation by Monamine oxidase (MAO). But those drugs are still substrates for COMT and this may affect duration of action of drug, a little.
 Specifically on ethyl group substitution, drug become more beta selective. Also CNS activity, oral activity and duration of action is increased.
Substitution on aromatic ring
 4'-OH is important for beta activity.
 3'-OH is important for alpha activity.
 Optimal activity on 3',4'-diOH : Both alpha and beta agonist activity. But easily metabolized by catechol-o-methyl transferase (COMT) thus oral activity is poor and short duration of action. Drug become hydrophilic which leads to poor CNS activity.
 3'-5'-diOH and 3'-CH2OH,4'-OH : Beta 2 selectivity is increased. Degradation by catechol-o-methyl transferase (COMT) is decreased thus drug absorption, oral activity and duration of action are increased.
