THEORETICAL-STUDY OF SELECTIVE H3-RECEPTOR ANTAGONISTS OF HISTAMINE

The conformations and charge distributions of three selective H3 receptor antagonists of histamine were determined using the MNDO approach. The results suggest that the conformational flexibilities of betahistine, Nalpha-(2-phenylacetyl)histamine and thioperamide are different; however, the low-energy conformations of these compounds show closely related spatial orderings. The MNDO calculations predict a significant population of the N1H form in the imidazole systems of Nalpha-(2-phenylacetyl)histamine and thioperamide. Our results indicate that the conformational behaviour of H3 antagonists is closely similar to that reported for H2 antagonists of histamine. These results emphasize the importance of tautomeric and electronic effects rather than conformational factors in accounting for the different antagonist activity at H2 or H3 receptors of several H2 ligands.