THE ROLE OF ELECTRONIC AND CONFORMATIONAL PROPERTIES IN THE ACTIVITY OF 5-HT(3)-RECEPTOR ANTAGONISTS

The conformational and electronic properties of 11 5-HT3 receptor anta gonists, were investigated to rationalize their biological activity. A ll compounds fulfill the previously reported geometrical requirements for the pharmacophore, although they show a wide spectrum of activitie s. Quantitative structure activity relationships (QSAR) models were se arched using the cross-validated partial least squares technique. The results of the QSAR analysis show that a unique model can rationalize both the in vitro (affinity, K(d)) and the in vivo (50% inhibitory dos e, ID50) activities. This model includes the value of the molecular el ectrostatic potential minimum above the aromatic fragment, used as an index of the pi-electron density, as well as the relative population o f the anti-periplanar (app, the ''active'') conformation. Two other mo dels were also obtained that include electrophilic superdelocalizabili ty indexes. Although these models give a more satisfactory value of th e cross-validated correlation coefficient (R(cv)2), they represent two different models for K(d) and ID50 which is in contrast with the expe rimental evidence that a correlation exists between these two activiti es. It is concluded that the use of electronic and conformational prop erties in addition to the geometrical characteristics may better descr ibe and predict the activity of 5-HT3 receptor antagonists, than the u se of geometrical characteristics alone.