Figure 10.
The design intention and surprising effects of some older drugs are known. Methadone and demerol were synthesized in an effort to make synthetically scalable anti-cholinergics as nerve gas antidotes by the Nazis in WWII. Their opioid effects were discovered serendipitously in a live cat assay. Imipramine was synthesized as an analog of other tricyclic anti-psychotics. Its surprising anti-depressive effects were discovered through direct human experimentation, later identified to result from inhibition of the serotonin reuptake transporter. Using 3D similarity, one can correctly associate the surprising target effects with the drugs, but using 2D similarity, one cannot.