Question

Propranolol is an adrenergic antagonist. Compare the structure of propranolol with noradrenaline and identify which features are similar in both molecules. Suggest why this molecule might act as an antagonist rather than an agonist.

Answer 1

Structures of propranolol and noradrenaline can be drawn as follows:

Both the molecules have identical functional groups as shown above. The asymmetric carbon bearing alcohol group has same configuration in both the molecules. Like adrenergic agonist noradrenaline, propranolol has hydroxyl and amino groups for polar interaction and aromatic groups for hydrophobic interaction.

Requirement for antagonist is that, it should bind to the receptor site as strong as agonist, but it should not activate the receptor. This is possible if after binding to receptor site compound fails to change the shape of receptor in desired way or it distorts the receptor in wrong way. This can also be achieved by extra interactions between receptor and ligand that produces a different induced fit compared with the interaction of receptor with natural ligand.

Thus, propranolol has bulky N-substitutent and bigger aromatic group (naphthyloxy) which can interact with additional sites in the receptor. Thus, a different induced fit may result accounting for the antagonist effect of propranolol.