Solution structure and dynamics of cyclic and acyclic cholinergic agonists

Two classes of nicotinic cholinergic agonists, which vary in flexibility and electronegativity, have been synthesized, and their structural and dynamic properties have been studied with nuclear magnetic resonance (NMR) spectroscopy. Although the compounds are chemically identical except for the presence or absence of one cyclicizing C--C bond, single channel recording and radioligand binding studies have shown that the cyclic compounds are considerably more potent than the acyclic derivatives (McGroddy, K.A., A.A. Carter, M.M. Tubbert, and R.E. Oswald. 1993. Biophys. J. 64:325-338). Using one- and two-dimensional NMR spectroscopy, we have shown that these molecules exist in two distinct stable conformers, which differ in the orientation of the amide bond. The cyclic 1,1-dimethyl-4-trifluoroacetyl-piperazinium iodide and its trifluoromethyl derivative compounds are symmetric, and the two conformers are of equal energy. The acyclic N,N,N,N'-tetramethyl-N'-acetylethylene-diamine iodide (TED) and its trifluoromethyl derivative derivatives, however, populate two energetically unequal solution conformations. Using variable temperature NMR spectroscopy on these molecules and their uncharged precursors, we have characterized the energetics of amide bond isomerization and have distinguished steric and electrostatic contributions to the equilibrium between the two conformers. The more populated TED conformer has the amide methyl group trans to the carbonyl oxygen, and it is stabilized by an electrostatic attraction between the partially negative carbonyl oxygen and the positively charged quaternary amine nitrogen. As discussed in the accompanying paper (McGroddy, K.A., A.A. Carter, M.M. Tubbert, and R.E. Oswald. 1993. Biophys. J. 64:325-338), the differences in the stable solution structures of the TED derivatives and their interconversion kinetics may be of biological significance.