Ring flexibility within tricyclic antidepressant drugs

J Pharm Sci. 2001 Jun;90(6):713-21. doi: 10.1002/jps.1027.


The internal flexibility 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 flexing. (1)H NMR line-shape analysis was used to obtain ring inversion barriers for 2-4. These studies yielded energy barriers of 14.3, 16.7, and 15.7 +/- 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 flexing associated with the central seven-membered ring for all four compounds. By fitting the T(1) data to a two-state jump model, lifetimes and amplitudes of rapid bridge flexing motions were determined. The results show that imipramine has the fastest rate of bridge flexing, followed by amitriptyline, doxepin, and dothiepin. The pharmacological profiles 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 difficult to rationalize their differing relative potency in different assays/clinical settings. However, the clear finding here that there are significantly 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.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Amitriptyline / chemistry
  • Antidepressive Agents, Tricyclic / chemistry*
  • Carbon Radioisotopes
  • Dothiepin / chemistry
  • Doxepin / chemistry
  • Imipramine / chemistry
  • Magnetic Resonance Spectroscopy
  • Molecular Conformation
  • Pliability
  • Temperature


  • Antidepressive Agents, Tricyclic
  • Carbon Radioisotopes
  • Doxepin
  • Amitriptyline
  • Imipramine
  • Dothiepin