The internal ¯exibility of the central seven-membered ring of a series of tricyclic antidepressant drugs (TCAs), imipramine {1}, amitriptyline{2}, doxepin {3}, and dothiepin {4}, has been investigated by 1 H and 13 C nuclear magnetic (NMR) techniques. Two dynamic processes were examined: ring inversion and bridge ¯exing. 1 H NMR lineshape analysis was used to obtain ring inversion barriers for 2±4. These studies yielded energy barriers of 14.3, 16.7, and 15.7 AE 0.6 kcal/mol for the hydrochloride salts of doxepin, dothiepin, and amitriptyline, respectively. The barriers for the corresponding free bases were lower by 0.6 kcal/mol on average. 13 C T 1 relaxation measurements were used to determine the degree of bridge ¯exing associated with the central sevenmembered ring for all four compounds. By ®tting the T 1 data to a two-state jump model, lifetimes and amplitudes of rapid bridge ¯exing motions were determined. The results show that imipramine has the fastest rate of bridge ¯exing, followed by amitriptyline, doxepin, and dothiepin. The pharmacological pro®les of the TCAs are complex and they interact with many receptor sites, resulting in numerous side effects and a general lack of understanding of their precise mode of action in different anxiety-related disorders. They all have similar three-dimensional structures, which makes it dif®cult to rationalize their differing relative potency in different assays/clinical settings. However, the clear ®nding here that there are signi®cantly different degrees of internal mobility suggests that molecular dynamics should be an additional factor considered when trying to understand the mode of action of this clinically important family of molecules.