PHARMACOLOGICAL PROFILE OF NEW THIOPERAMIDE DERIVATIVES AT HISTAMINE PERIPHERAL H1-RECEPTORS, H2-RECEPTORS, H3-RECEPTORS IN GUINEA-PIG

The recent availability of potent and selective ligands, namely R-(alpha)-methylhistamine and thioperamide, led to conclusive progresses as regards histamine H-3-receptor knowledge. The aim of this work is to investigate by in vitro tests the pharmacological properties of new amino and methyl derivatives of the H-3-antagonist thioperamide. Such original compounds, developed by the modulation of the thioperamide imidazolyl moiety, were assayed at guinea-pig ileal contractile H-1-, atrial chronotropic H-2- and enteric neuronal H-3-receptors. None of the drugs exhibited interaction with H-1 or H-2 sites. On electrically stimulated ileum, two of the thioperamide methyl derivatives competitively antagonized the inhibitory effect of the H-3-agonist R-(alpha)-methylhistamine. On the basis of the Schild analysis, the more active isomer (compound IV) displayed an affinity at H-3-receptors only five times lower than thioperamide. These results could contribute to elucidate further the structural features required to develop potent and selective H-3-antagonists. On the other hand, to prove the hypothesized apparent heterogeneity between peripheral and central H-3-sites, as emerged by pharmacological and binding studies, autoradiographic investigations are in progress.