Substituent Effect in Histamine and Its Impact on Interactions with the G Protein-Coupled Human Receptor H1 Modelled by Quantum-Chemical Methods

Neutral and protonated histamine tautomers, mono-substituted with twelve functional groups, were studied theoretically as isolated molecules and complexes with the H₁ receptor. Geometry and energy of tautomers were optimized using the DFT method with the B3LYP functional and the aug-cc-pVTZ basis set. The approach was based on the charge of the substituent active region (cSAR) parameters and the Harmonic Oscillator Model of Aromaticity (HOMA) indices. The cSAR parameters characterized the electron density better than the conventional Hammett's constants <i>σ</i>. In general, the cSAR parameters correlate with other characteristics of the charge distribution, particularly those for substituents at the carbon atom in the ring adjacent to the side chain. Substituents at this atom affected the aromaticity less strongly than those located between two nitrogen atoms, which confirmed recent reports. Our results suggest that the 3H tautomer isomerizes into the 1H one after binding to the H₁ receptor. Moreover, the electron structure of the molecule hydrogen-bonded to the receptor may significantly depend on the electron donor-acceptor properties of the substituent. The strong electron-accepting substituents, e.g., NO₂, favor the imidazole configuration of the ring in the bonded molecule, while the strong electron-donating ones, e.g., NH₂, promote the imidazolium one.