Theoretical studies on tricyclic antidepressants: III. Analysis of stereospecificity.

By dynamic simulation of molecular structures in a digital computer, search was made for all possible ways of superposing a phenyl ring of a tricyclic antidepressant on the phenyl ring of norepinephrine. Using all available structure activity data and deductive reasoning, attempt was then made to reject all but one superposition. A significant outcome was information regarding 2-hydroxydesipramine. Although manifestly inactive when administered, this drug is likely to be potent if delivered at the neuronal site of action. From the chosen superposition a dihydroxy derivative is predicted to be even more potent if it can be endogenously generated or suitably modified to enable delivery at the site of action. Among the various superpositions obtained, it was indirectly possible to make a Monte Carlo type of conformational analysis on the side chain of norepinephrine. Previous conformational studies on norepinephrine are reviewed in this context.