From hit to lead. Combining two complementary methods for focused library design. Application to mu opiate ligands

Compound 1 obtained by random screening and displaying a micromolar activit y on the At opiate receptor was chosen as a starting point for optimization . Two complementary concepts of similarity were used for the design of anal ogues and compared. These are based, respectively, on a computer-aided comp arison of pharmacophoric patterns and on topological similarity. The struct ure-activity relationships are discussed in light of both similarity concep ts. Compound 40, an N-methyl-3-(4-oxo-1-phenyl-1,3,8-triazaspiro[4.5]decyl) acetamide derivative, designed by combining the structure-activity relation ships enlightened by each method, has a subnanomolar affinity for mu (h) re ceptor (IC50 = 0.9 nM). It is a promising lead, allowing the design of a ne w series of analogues substituted at the N-3 of the spirocycle moiety.