¹³C NMR studies of the solution molecular dynamics of tricyclic antidepressants

Abstract

"C NMR spin-lattice relaxation times (T,s) and nuclear Overhauser enhancements (NOE's) were measured for a series of clinically used tricyclic antidepressants (TCAs), imiprarnine (l), amitriptyline (2), doxepin (3) and dothiepin (4), at two magnetic field strengths (corresponding to "C frequencies of 75 and 100 MHz). The measurements were carried out at a range of solution concentrations in CDCI, and D,O in order to determine the factors that influence overall and internal molecular dynamics in these systems. Both the hydrochloride salts and free bases were examined. For solutions in CDCI, over a range of concentrations, or for lowconcentration (0.03 M) solutions in D,O, T, and NOE measurements were independent of magnetic field strength, indicating that motion of the TCAs was in the 'extreme narrowing limit.' In contrast, for 0.3 M solutions of the hydrochloride salts in D,O, T , and NOE measurements were field dependent, indicating the presence of significantly slower molecular mobility. It is proposed that micelles are present at this concentration and are responsible for reduced overall tumbling of the TCAs. Several degrees of internal motion were detected by the relaxation and T, measurements, viz. rapid flexing motion of the benzylic bridging carbons in the central seven-membered ring and segmental motion of the sidechain. From an examination of the effect of solvent, concentration and protonation state of the side-chain on the latter motion, it was possible to derive information on side-chain conformations and interactions.

NMR characterization of the host–guest inclusion complex between β‐cyclodextrin and doxepin

“…[2,3] Ring inversion involves global reorientation of the molecule and occurs on the millisecond timescale, while the flexing of the bridge occurs on the nanosecond time scale. [2] At higher concentrations, dimethylamine groups at the end of the alkyl tails of two different doxepin molecules are thought to interact to form a dimer, placing the two methyl groups in different chemical environments, as evidenced by a concentration-dependent broadening of the methyl 1 H NMR resonances due to intermediate chemical exchange. [1,4] The dimethylamine group can also interact electrostatically with negatively charged molecules to create conditions in which the methyl resonances slowly exchange between different chemical environments.…”

“…[2] At higher concentrations, dimethylamine groups at the end of the alkyl tails of two different doxepin molecules are thought to interact to form a dimer, placing the two methyl groups in different chemical environments, as evidenced by a concentration-dependent broadening of the methyl 1 H NMR resonances due to intermediate chemical exchange. [1,4] The dimethylamine group can also interact electrostatically with negatively charged molecules to create conditions in which the methyl resonances slowly exchange between different chemical environments. [1] Cyclodextrins are an important class of molecules used as drug excipients, [6 -8] and as mobile phase modifiers in separation techniques such as capillary electrophoresis and HPLC.…”

“…[1,4] The dimethylamine group can also interact electrostatically with negatively charged molecules to create conditions in which the methyl resonances slowly exchange between different chemical environments. [1] Cyclodextrins are an important class of molecules used as drug excipients, [6 -8] and as mobile phase modifiers in separation techniques such as capillary electrophoresis and HPLC. [9,10] These applications rely on the ability of cyclodextrins to form inclusion complexes.…”

Mechanisms and Surface Chemical Prediction of Imipramine ‐Induced Hemolysis Suppressed by Modified Cyclodextrins

“… Chemical structures of (a) imipramine hydrochloride (IMP)17, 18 and (b) α‐CD ( n = 6, R 1 = R 2 = R 3 = H), β‐CD ( n = 7, R 1 = R 2 = R 3 = H), γ‐CD ( n = 8, R 1 = R 2 = R 3 = H), CM ( n = 7, R 1 = R 2 = H, R 3 = H or CH 2 COONa), DM ( n = 7, R 1 = R 3 = CH 3 , R 2 = H), G 1 ( n = 7, R 1 = R 2 = H, R 3 = H or glucosyl), G 2 ( n = 7, R 1 = R 2 = H, R 3 = H or maltosyl), HP ( n = 7, R 1 = R 2 = R 3 = H or CH 2 CH(OH)CH 3 ), and S ( n = 7, R 1 = R 2 = R 3 = H or SO 4 Na). …”

“…Imipramine hydrochloride (IMP), a tricyclic antidepressant (Figure 1a),17,18 causes hemolysis when injected intravenously. The hemolysis of this drug can be reduced by β‐ and γ‐CDs, but this is not the case of α‐CD 19.…”