Identification of 5-hydroxytryptamine1A receptor agents using a composite pharmacophore analysis and chemical database screening.

A composite pharmacophore analysis and computer-assisted chemical database screening were used to identify a previously unrecognized class of 5-hydroxy-tryptamine1A (5-HT1A) receptor active agents. An analysis of published data led to the identification of 20 different chemical structures which share nanomolar affinity for the 5-HT1A receptor. From a composite pharmacophore analysis of all 20 potent agents, we hypothesized that compounds containing a novel (in terms of 5-HT1A receptor analysis) 3 ring structure might be active at the 5-HT1A receptor. To test this hypothesis, the Chemical Abstracts database, which contains over 10 million compounds, was screened electronically for compounds that contain this core structure. A series of 319 agents was identified which contain this core structure. A total of 6 compounds was then obtained commercially and evaluated in radioligand binding studies. A single agent (Compound 69/183) conformed most closely to the composite 5-HT1A pharmacophore and displayed an affinity of 20 nmol/l for the 5-HT1A receptor binding site. Two other agents displayed affinities of 170 and 500 nmol/l, respectively, for the 5-HT1A receptor site. The 3 agents which differed most significantly from the composite 5-HT1A pharmacophore displayed affinities of 1,200- greater than 10,000 nmol/l for the 5-HT1A receptor binding site. These data suggest that a composite pharmacophore analysis and computer-assisted chemical database screening can be an effective technique for the identification of previously unrecognized receptor active agents.