Conformation of histamine derivatives. 5. Molecular orbital calculation of the H1-receptor "essential" conformation of histamine.

Conformational energies of histamine and 4-methylhistamine monocations are calculated using the EHT molecular orbital procedure; the results are expressed as potential energy surfaces in which bond rotations (theta1 for ring-Cbeta, theta2 for Cbeta-Calpha) are measured along the axes, and energy variation is indicated by contours. Using the classical Boltzmann partition function and Simpson's rule for normalization, corresponding probability surfaces are generated which take account of the potential surface entropy. Comparing the two surfaces provides regions which are within a given probability contour of histamine but outside this contour for 4-methylhistamine. Thus, at the 99% probability level, three conformational regions defined by the bond rotation angles are indicated as possible "H1-essential" conformations of histamine: viz. trans (theta1=290-330 degrees, theta2=150-210 degrees) and gauche (theta1=260-280 degrees, theta2=30-90 degrees and theta1=290-320 degrees, theta2=270-320 degrees). This procedure provides a quantitative basis for comparison with other histamine derivatives and may have a general value for studying relationships between conformation and biological activity of closely related small molecules.