Structure Activity Relationship

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Chapter: Medicinal Chemistry : Adrenergic Blockers

Propranolol has become one of the most thoroughly studied and widely used drug in the therapeutic armamentarium; it is the standard against which all other β antagonists are compared.


STRUCTURE-ACTIVITY RELATIONSHIP

Propranolol has become one of the most thoroughly studied and widely used drug in the therapeutic armamentarium; it is the standard against which all other β antagonists are compared.


  • The aromatic ring and its substituent is the primary determinant of β1 antagonistic activity. The aryl group also affects the absorption, excretion, and metabolism of the β blockers.

  • β blockers are structurally similar to β agonist. The catechol ring can be replaced by a variety of ring system without loss of antagonistic activity.

  • Replacement of catechol hydroxyl group with chlorine of phenyl ring system retains β blocking activity. Example: pronethalol, dichloroisoproterenol.

  • N, N–disubstitution decreases the β blocking activity, and the activity is maintained when the phenyl ethyl, hydroxy phenyl ethyl, or methoxy phenyl ethyl groups are added to amine as a part of the molecule.

  • The two carbon chains are essential for activity.

  • The introduction of –OCH2 group into the molecule between the aromatic ring and the ethyl amine side chain provides β blocking agents, for example, propranolol.

  • As in the sympathomimetics, bulky aliphatic groups, such as the tert-butyl and isopropyl groups are normally found on the amino function of the aryloxypropanolamine β receptor antagonists. It must be a secondary amine for optimal activity.

  • As with the sympathomimetic agents, the configuration of the hydroxyl bearing carbon of the aryloxypropanolamine side chain play a critical role in the interaction of β antagonist drugs with β receptor. The carbon must possess the (S) configuration for optimal affinity to the β receptor. The enantiomer with the (R) configuration is typically 100 times less potent.

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