2.  It is generally believed that the o,o’-dichloro-substituents in clonidine can be replaced by a methyl group without losing any potency or selectivity. However, the resulting compound possesses a shorter duration of action, why?

 

Ans: A methyl group is approximately similar in size (volume) as a chlorine atom. Thus, it will exhibit similar steric interactions to force the ring to assume proper conformation for binding to the a2 receptors. Thus, replacement of chlorine in the clonidine will retain its agonist potency. However, an aromatic methyl group will be metabolized by the cytochrome P-450 enzyme to the corresponding hydroxymethyl and then to the carboxylic acid group which are both inactive at the a2 receptors. Thus the methyl analogue will have a shorter duration of action.