THEORETICAL ANALYSES OF THE TAUTOMERIC AND CONFORMATIONAL EQUILIBRIA OF HISTAMINE AND (ALPHA-R,BETA-S)-ALPHA,BETA-DIMETHYLHISTAMINE IN THE GAS-PHASE AND AQUEOUS-SOLUTION

Ab initio calculations in the gas phase and Monte Carlo simulations us ing the statistical pertubation method in aqueous solution have been c arried out to study the tautomeric/conformational equilibria of histam ine and (alpha R,beta S)-alpha,beta-dimethylhistamine in both the neut ral and protonated forms. The two most stable gas-phase conformers of the neutral histamine molecule are gauche structures stabilized by int ramolecular hydrogen bonds. The gauche 1H tautomer is more stable than the gauche 3H structure by 1.7-1.8 kcal/mol at the QCISD/6-31 G//HF/ 6-31G and MP2/ 6-311++G**//HF/6-3 1G* levels after considering freque ncy dependent corrections for the free energy at 298 K. Trans conforme rs at these levels are higher in free energy than gauche 1H by 2.3-3.7 kcal/mol. For the monocations protonated at the side chain the second most stable trans 3H form is higher in free energy by 13 kcal/mol tha n the most stable gauche 3H structure. The relative free energies of t he protonated g1H and t1H tautomers are 19-25 kcal/mol. (alpha R,beta S)-alpha,beta-Dimethylation of histamine has an effect mainly on the e quilibrium geometries leaving the relative energies close to those obt ained for histamine. For the equilibrium mixture of the neutral forms (existing at pH > 9-10 in aqueous solution) 87% trans and 13% gauche c onformers were calculated for histamine. The preference for the trans over the gauche conformations may be attributed to the larger number o f polar sites opened for hydration in aqueous solution. In the monocat ionic form prevailing under physiological conditions at pH = 7.4, the gauche 3H tautomer is more stable than the trans 1H structure by about 0.4 kcal/mol leading to 64% gauche and 36% trans conformers. This res ult is in good agreement with previously reported NMR results in solut ion at pD = 7.9 that predicted 45% trans form. For both the histamine and the (alpha R,beta S)-alpha,beta-dimethylhistamine solutes the gauc he 3H solute is more stable than the trans 3H conformer by about 2 kca l/mol. The theoretical calculations highlight the balance of the inter nal stabilization and the solvent effect. Solution structure analysis provides rationale for the energy changes in the tautomerization proce sses and conformational changes upon solvation. The results are discus sed in relationship to existing models for histamine receptor activati on.