Page 214 - Medicinal Chemistry Self Assessment

2.21 Phenobarbital and Other Barbiturates 203

These metabolites would not be expected to retain the pharmacological activity that was present in
the parent drug molecules. For any drug molecule to produce a pharmacological effect, it needs to
contribute complementary interactions with its biological target. The alkyl chains and aromatic ring
are important for forming van der Waals and hydrophobic interactions with hydrophobic amino acids
within the GABA receptor. The addition of hydrophilic functional groups at this position decreases
A
their ability to form these key interactions. Furthermore, the addition of these hydrophilic functional
groups in the liver would greatly decrease or eliminate the ability of these metabolites to cross the
blood–brain barrier and reach their site of action in the CNS.