THEORETICAL PROTON AFFINITIES OF HISTAMINE, AMTHAMINE AND SOME SUBSTITUTED DERIVATIVES

We have characterized tautomers and conformers (T/Cs) of 4-methyl, 4-c hloro, 4-nitro, N-alpha methyl histamines (4(5)-2'-aminoethylimidazole ), amthamine (2-amino-5-(2' -aminoethyl)-4-methylthiazol) and amthamin e derivatives (2-amino-5-(2'-aminoethyl)-thiazole, and 4-methyl-5-(2'- aminoethyl)-thiazole) neutral and as monocations by means of the RHF w avefunctions at the 6-31G*//6-31G** level, using analytical gradients . All these compounds are agonists of the HZ receptors of histamine. M ost stable T/Cs of histamine derivatives are gauche with an internal h ydrogen bond (HyB).These HyBs have been characterized with the help of the topological analysis of the charge density. Monocations are also gauche with stronger HyBs, in both N-(1,N-3)-H and N-(3)-H tautomers. Amthamine and amthamine derivatives show trans conformations as the mo st stable structures. N(3)-H gauche monocations are the most stable st ructures, gauche conformers present electrostatic internal interaction s characterized by means of topological analysis of the charge density , giving bond critical points. We have calculated proton affinity (PA) differences relative to ammonia with the help of isodesmic reactions. All histamine derivatives are strong bases in the gas phase, especial ly methyl derivatives. Amthamine yields a conformer structure and PA v ery close to that of the histamine. Two other amthamine derivatives yi eld lower PAs than that of amthamine. Reactivity of histamine as well as substituent effects are discussed. Possible interactions with the H -2 receptors of histamine are also discussed. (C) 1998 Elsevier Scienc e B.V. All rights reserved.