Three-dimensional steric molecular modeling of the 5-hydroxytryptamine3 receptor pharmacophore.

A computer-based three-dimensional steric molecular model of the 5-hydroxytryptamine3 (5-HT3) receptor pharmacophore was defined on the basis of radioligand binding data. Analysis of published data led to the identification of 19 different chemical structures that share only a single known pharmacological property, i.e., less than 10 nM affinity for the 5-HT3 receptor. These 19 compounds were then categorized into seven chemical families, which derive from six main steric "core" structures. From the composite analysis of all 19 potent agents, nine steric chemical criteria were derived, which can be used to describe the 5-HT3 receptor pharmacophore. This information was then used to explain the 5-HT3 receptor inactivity of atrophine, a compound that differs structurally from ICS 205-930 in the steric properties of only a single key atom. The steric chemical information was also used to predict the activity of serotonergic compounds that had never been analyzed at 5-HT3 receptor binding sites. Two serotonergic drugs that meet all nine steric criteria were found to be active at the 5-HT3 receptor binding site (i.e., pizotifen, KI = 42 +/- 10 nM, and clozapine, KI = 52 +/- 8 nM). By contrast, two serotonergic agents that do not meet the criteria were found to be inactive at the 5-HT3 receptor binding site (i.e., ipsapirone and pirenperone, KI values greater than 1000 nM). This computer-based steric molecular modeling approach allows for the analysis and identification of 5-HT3 receptor-active agents with minimal dependence upon animals and radioactive compounds.