DEVELOPMENT OF 5-HT1A RECEPTOR ANTAGONISTS

The discovery that non-benzodiazepine anxiolytic agents such as buspir one bind with high affinity to the 5-HT1A receptor has stimulated the development of selective 5-HT1A receptor ligands as potential drug can didates. However, the lack of selective 5-HT1A receptor antagonists ha s hampered the elucidation of the mechanism of action of these agents, indeed, it is still unclear whether buspirone exerts its anxiolytic e ffects via an agonist action at presynaptic (somatodendritic) or an an tagonist action at postsynaptic 5-HT1A receptors. Ligands that have be en used previously to define the 5-HT1A receptor are either son-select ive or have agonist activity at the presynaptic 5-HT1A receptor. It is only in the past three years that selective and silent 5-HT1A recepto r antagonists have emerged. This overview compares the profiles of the first selective 5-HT1A receptor antagonists in models of pre- and pos tsynaptic 5-HT1A receptor function. In addition, it highlights some of the problems associated with the development of selective 5-HT1A rece ptor antagonists.