Modeling amphetamine/receptor interactions: a gas-phase study of complexes formed between amphetamine and some chiral amido[4]resorcinarenes

Amphetamine (A) and its analogues are central nervous system stimulants. Their enantiomers show different pharmacological properties: both D-amphetamine and L-amphetamine are thought to exert their effects by binding to the monoamine transporters and increasing extracellular levels of the biogenic amines, such as dopamine, norepinephedrine and serotonin. The mechanisms of action of D- or L-A proceed through preliminary interactions with the amino acids of the N terminus of human dopamine transporter (or their phosphorylated forms). In view of the complexities of the monoamine uptake processes, our purpose is to investigate the nature of the noncovalent interactions between the enantiomers of A and some artificial receptors (M) containing different amino acidic groups in the gas phase under conditions mimicking the extensive desolvation accompanying the uptake of amphetamine inside the receptor cavity. The molecular asymmetry of the selected host M is due to the four dissymmetric pendants, which may be spatially oriented so as to generate chiral cavities of different size and shape. We have also taken into account the effect of size, hindrance and flexibility of lateral pendants by using different chiral host molecules. In addition we evaluated the effects of anion Cl- on the substrate recognition step that impacts the entire uptake process. We performed specific experiments in the gas phase, where interference from the solvent and the counterion is excluded and direct comparison with computational studies is allowed. The enantioselectivities of the selected M hosts towards the A enantiomers were checked by introducing the proton-bonded two- [M·H·A]+ or three- [M·H·(A)2·HCl]+ body complexes into a Fourier Transform Ion Cyclotron Resonance Mass Spectrometer (FT-ICR-MS), fitted with an electrospray ionization source (ESI), and by measuring the rate of the displacement reactions with (R)-(-)-but-2-ylamine or (S)-(+)-but-2-ylamine. In conclusion the experimental results were compared with accurate theoretical studies by approaching the conformational picture with docking and molecular dynamic runs.