Pharmacological characterization of H3 receptor antagonists with imidazole, thioimidazole and thioimidazoline polar groups in the side chain.

Abstract

The third histamine receptor, initially seen as a central presynaptic autoreceptor, is currently recognised as an auto and heteroreceptor with the function of a general inhibitory brake in the cellular communications in neuronal and extraneuronal tissues [1]. The evidence that the H3 receptors are widely distributed in the brain and that they are tonically activated by histamine opened important perspectives for potential applications of H3-ligands in the treatment of different central disorders. The most recent data seem to indicate that H3 antagonism can favourably influence cognitive and learning functions, can normalize motor disturbances and can represent a new approach for the development of antiepileptic and antiobesity drugs [2]. Several H3 antagonists have been developed, but there remains a need to identify new molecules combining improved brain penetration, tolerability and good receptor affinity and selectivity. Proceeding from the study evaluating the pharmacological properties of original H3 blockers [3], we characterized in vitro the potency, affinity and selectivity at H3 histamine receptors of a series of imidazole derivatives with different degrees of basicity due to the presence of distinct polar groups in the side chain of variable length (Table 1). Further in vitro tests were performed to assess the possible interactions of the compounds at the guinea-pig ileal 5-HT3, a2 and M3 receptors.