4-(omega-(alkyloxy)alkyl)-1H-imidazole derivatives as histamine H(3) receptor antagonists/agonists.

In an effort to develop new histamine H(3) receptor antagonists usable as pharmacological tools we present here novel unsymmetrical ether derivatives. Etherification of different omega-(1H-imidazol-4-yl)alkyl scaffolds led to compounds containing alkyl chains of increasing lengths either with or without unsaturated termini, cycloalkyl or arylalkyl moieties, or additional heteroatoms. When investigated in an in vitro assay on rat synaptosomes, the majority of compounds displayed potencies in the low nanomolar concentration range at the H(3) receptor, e.

Replacement of imidazole by a piperidine moiety differentially affects the potency of histamine H3-receptor antagonists.

We examined whether replacement of imidazole by a piperidine or pyrrolidine moiety will affect the potency and affinity of six H3-receptor antagonists. Potencies were determined in superfused mouse brain cortex slices preincubated with [3H]noradrenaline, in which the interaction of the antagonists with histamine with respect to its inhibitory effect on the electrically evoked tritium overflow was studied. Affinities were determined in mouse brain cortex membranes, using the radioligand [3H] N(alpha)-methylhistamine.

Piperidino-hydrocarbon compounds as novel non-imidazole histamine H(3)-receptor antagonists.

In search for novel non-imidazole histamine H(3)-receptor antagonists, piperidino-hydrocarbon compounds were synthesized using the known non-imidazole histamine H(3)-receptor antagonist FUB 637 (3-phenylpropyl 3-piperidinopropyl ether) as lead structure. Piperidino-alkyl derivatives containing highly flexible side chains (2, 4-7) were prepared via N-alkylation. Compounds containing unsaturated alkyl groups were synthesized in order to investigate the impact of rigidifying the side chain (8-16).