Molecular determinants for recognition of triazole and tetrazole analogs of histamine at H2-receptors.
Calculations of molecular structures, relative stabilities of the various tautomers, and molecular electrostatic potentials (MEPs) were used to examine the molecular properties that determine the actions at H2-receptors of histamine analogs in which the imidazole ring was replaced by triazole or tetrazole. The analysis indicates that the most stable tautomer of 3-ethylamine-1,2,4-triazole (EATRI), is also the most similar to the assumed active form of histamine. Differences in the MEP of EATRI and histamine are observed mainly near the N(2) nitrogen of EATRI which is the steric equivalent of the C(4) position of histamine. Because EATRI is recognized at the receptor in spite of these differences, we conclude that the H2-receptor has no selectivity with respect to the electrostatic or steric properties near this position, in agreement with previous observations from structure-activity relations. This conclusion contrasts with the apparent selectivity of the receptor for the reactivity properties of the position equivalent to C(2) in histamine. Thus, the analysis of the tautomeric forms and MEP of the 5-ethylamine-1,2,3,4-tetrazole, which is not recognized by the H2-histamine receptor, suggests that the negative potential near the N(3) nitrogen, which corresponds to C(2) in histamine, is responsible for the inactivity of this molecule. The mechanism of receptor activation by EATRI is analyzed in relation to results from a theoretical simulation of a proposed activation mechanism of H2-histamine receptors. We find that the discriminant property for receptor activation by EATRI should be the relative energy of the ring protonated tautomers, and our results indicate that only the cation in which the ring protonation is on N(1) and N(4) and the side chain is anchored at the negative receptor site can be recognized at the histamine H2-receptor, and can participate in the proposed activation process.
D001393:Azoles / Q000378:metabolism*; D006632:Histamine / Q000031:analogs & derivatives* / Q000378:metabolism; D008958:Models, Molecular; D011970:Receptors, Histamine H2 / Q000378:metabolism*; D013237:Stereoisomerism; D013329:Structure-Activity Relationship; D013777:Tetrazoles / Q000378:metabolism*; D014230:Triazoles / Q000378:metabolism*
D001393:Azoles; D011970:Receptors, Histamine H2; D013777:Tetrazoles; D014230:Triazoles; D006632:Histamine