Structural Features and Hydrogen-Bond Properties of Galanthamine and Codeine: An Experimental and Theoretical Study

Structural features of galanthamine and codeine, two allosteric potentiating ligands of nicotinic acetylcholine receptors (nAChRs), have been investigated through experimental studies in solution by FTIR and NMR spectroscopy and by quantum chemical calculations in the isolated state. The infrared spectra accumulated in solvents of various polarities show that the intramolecular OH center dot center dot center dot O hydrogen bond in galanthamine is stronger than the corresponding interaction in codeine. Molecular electrostatic potential calculations allow rationalisation of the experimental trends. NOE measurements on the two ligands in the same solvent range show significant differences. In apolar solvents, the NMR spectroscopic data indicate the occurrence of CH center dot center dot center dot O hydrogen-bond interactions, whereas in the more polar solvents, a trans orientation of the methoxy group with respect to the furanyl oxygen atom is favoured. A natural bond orbital (NBO) analysis provides evidence that these stabilising interactions originate in the hyperconjugation between the lone pairs of the furanyl oxygen atoms, n(O), and the methoxy anti-bonding sigma*(C-H) orbitals within the two molecules. Despite the strong structural similarities between the two allosteric modulators, FTIR equilibrium constants measurements of hydrogen-bond complexation combined with quantum chemistry calculations point out the significant increase of hydrogen-bond accepting strength of galanthamine relative to codeine. This increase is mainly assignable to the stronger hydrogen-bond basicity of the hydroxyl group, and to a lesser extent to the higher hydrogen-bond accepting strength of the amino nitrogen of galanthamine in comparison with the corresponding groups of codeine. An analysis of the interactions that occur between the two ligands and acetylcholine esterase (AChE) suggests significant differences with Trp84, a key component of the AChE catalytic active site. In contrast, both ligands appear to interact similarly with acetylcholine binding protein (AChBP).