Fluorescent ligands for the histamine H2 receptor: synthesis and preliminary characterization.

3-[3-(Piperidinomethyl)phenoxy]alkyl, N-cyano-N'-[omega-[3-(1-piperidinylmethyl)phenoxy]alkyl]guanidine and 2-(5-methyl-4-imidazolyl)methyl thioethyl derivatives containing fluorescent functionalities were synthesized and the histamine H2 receptor affinity was evaluated using the H2 antagonist [125I]-aminopotentidine. The compounds exhibited weak to potent H2 receptor affinity with pKi values ranging from <4 to 8.85. The highest H2 receptor affinity was observed for N-cyano-N'-[omega-[3-(1-piperidinylmethyl)phenoxy]alkyl]guanidines substituted with methylanthranilate (13), cyanoindolizine (6) and cyanoisoindole (11) moieties via an ethyl or propyl linker.

Improgan antinociception does not require neuronal histamine or histamine receptors.

Improgan, a chemical congener of the H(2) antagonist cimetidine, induces antinociception following intracerebroventricular (i.c.v.) administration in rodents, but the mechanism of action of this compound remains unknown. Because the chemical structure of improgan closely resembles those of histamine and certain histamine blockers, and because neuronal histamine is known to participate in pain-relieving responses, the antinociceptive actions of improgan were evaluated in mice containing null mutations in the genes for three histamine receptors (H(1), H(2), and H(3)) and also in the gene for histidine decarboxylase (the histamine biosynthetic enzyme). Similar to earlier findings in Swiss-Webster mice, improgan induced maximal, reversible, dose-related reductions in thermal nociceptive responses in ICR mice, but neither pre-improgan (baseline) nor post-improgan nociceptive latencies were changed in any of the mutant mice as compared with wild-type controls. Improgan also had weak inhibitory activity in vitro (pK(i)=4.7-4.9) on specific binding to three recently-discovered, recombinant isoforms of the rat H(3) receptor (H(3A), H(3B), and H(3C)). The present findings strongly support the hypothesis that neuronal histamine and its receptors fail to play a role in improgan-induced antinociception.