Development of 5-HT1A receptor antagonists

The discovery that non-benzodiazepine anxiolytic agents such as buspirone bind with high affinity to the 5-HT1A receptor has stimulated the development of selective 5-HT1A receptor ligands as potential drug candidates. However, the lack of selective 5-HT1A receptor antagonists has hampered the elucidation of the mechanism of action of these agents, indeed, it is still unclear whether buspirone exerts its anxiolytic effects via an agonist action at presynaptic (somatodendritic) or an antagonist action at postsynaptic 5-HT1A receptors. Ligands that have been used previously to define the 5-HT1A receptor are either non-selective or have agonist activity at the presynaptic 5-HT1A receptor. It is only in the past three years that selective and silent 5-HT1A receptor antagonists have emerged. This overview compares the profiles of the first selective 5-HT1A receptor antagonists in models of pre- and postsynaptic 5-HT1A receptor function. In addition, it highlights some of the problems associated with the development of selective 5-HT1A receptor antagonists.