Search for novel leads for histamine H3-receptor antagonists: amine derivatives
Stark, H.; Ligneau, X.; Lipp, R.; Arrang, J.M.; Schwartz, J.C.; Schunack, W.
Die Pharmazie 52(6): 419-423
1997
ISSN/ISBN: 0031-7144 PMID: 9260265 Document Number: 474880
In search for novel leads for histamine H-3-receptor antagonists a number of amine derivatives of different (1H-imidazol-4-yl)anilines and omega-(1H-imidazol-4-yl)alkanamines were prepared. Pharmacological in vitro H-3-receptor investigations of the prepared urea, amide, inverse amide, thioamide, and thiourea derivatives on synaptosomes of rat cerebral cortex proved that the aniline derivatives are inactive at H-3-receptors, whereas derivatives of the omega-(1H-imidazol-4-yl)-alkanamines showed moderate to good activity. Some compounds are active in the nanomolar concentration range. The most potent compounds in this series are the thioamide derivative 7 and the urea derivatives 11, 12 of 3-(1H-imidazol-4-yl) propanamine. Therefore, the urea derivatives were tested in vitro on isolated organs of the guinea pig for their activity on the other two histamine receptor subtypes proving their high selectivity. In vivo studies of the effects of the urea derivatives 11 and 12 on brain N-tau-methylhistamine levels, a test of central H-3-receptor activity after peroral application to mice, showed no detectable activity. Thus, the urea type antagonists are useful potent and selective H-3-receptor tools for in vitro studies and for investigations of ligand-receptor interactions.