From hit to lead. Analyzing structure-profile relationships

Two compounds, obtained by random screening, and displaying micromolar acti vities on the At opiate receptor were used as starting points for optimizat ion. In that work, the traditional concept of the activity of a compound (r elated to one or a few targets) was extended to the comprehensive pharmacol ogical profile of that compound on more than 70 receptors, transporters, an d channels relevant to a CNS-oriented project. Using the two complementary design strategies based on two similarity concepts described in the previou s paper, we have obtained analogues with IC50 values ranging between 0.9 nM and a few micromolar on the mu receptor and displaying qualitatively diffe rent profiles. We discuss here, both on a case-by-case basis and from a sta tistical standpoint, the pharmacological profiles in light of the two simil arity concepts.