title: In vitro and in vivo pharmacological analysis of imidazole-free histamine H3 receptor antagonists: promising results for a brain-penetrating H3 blocker with weak anticholinesterase activity.
abstract: The pharmacological profiling of potent histamine H(3)-ligands initiated in a previous study is completed here. In vitro functional and binding studies revealed that several derivatives were selective H(3)-antagonists with nanomolar potency at human and guinea-pig histamine receptors, able to inhibit rat brain cholinesterase at micromolar concentrations and devoid of any cytotoxicity on cultured cells. Ex vivo binding experiments in rats showed that the most potent H(3)-antagonist, compound 5, had a prompt and long-lasting presence in the central nervous system (CNS), inhibiting [(3)H](R)-alpha-methylhistamine cortical binding [ED(50) (dose that elicits a 50% response) = 0.63 mg/kg intraperitoneally (i.p.)]. In the passive-avoidance test, compound 5, at 1.25 mg/kg i.p., was as effective as the anti-Alzheimer drug donepezil in attenuating scopolamine-induced amnesia in rats. These results suggest that a good CNS penetration and multitarget activity could account for the antiamnesic effect of this weak cholinesterase inhibitor and potent H(3)-antagonist (compound 5). This result represents a potential benchmark for the development of non-imidazole H(3)-antagonists/cholinesterase inhibitors with therapeutic potential in cognitive disorders.
authors.affiliation: Dipartimento di Scienze Farmacologiche, Biologiche e Chimiche Applicate, Università di Parma, Parma, Italy.
authors.forename: Simona
authors.initials: S
authors.lastname: Bertoni
authors.forename: Vigilio
authors.initials: V
authors.lastname: Ballabeni
authors.forename: Lisa
authors.initials: L
authors.lastname: Flammini
authors.forename: Francesca
authors.initials: F
authors.lastname: Saccani
authors.forename: Giuseppe
authors.initials: G
authors.lastname: Domenichini
authors.forename: Giovanni
authors.initials: G
authors.lastname: Morini
authors.forename: Mara
authors.initials: M
authors.lastname: Comini
authors.forename: Mirko
authors.initials: M
authors.lastname: Rivara
authors.forename: Elisabetta
authors.initials: E
authors.lastname: Barocelli
mesh_terms: D000818:Animals; D001362:Avoidance Learning / Q000187:drug effects; D001921:Brain / Q000378:metabolism*; D002470:Cell Survival / Q000187:drug effects; D002478:Cells, Cultured; D002800:Cholinesterase Inhibitors / Q000378:metabolism*; D003627:Data Interpretation, Statistical; D004558:Electric Stimulation; D006168:Guinea Pigs; D006321:Heart / Q000187:drug effects; D054828:Histamine H3 Antagonists / Q000493:pharmacokinetics* / Q000494:pharmacology*; D006801:Humans; D007082:Ileum / Q000187:drug effects; D007093:Imidazoles / Q000737:chemistry; D066298:In Vitro Techniques; D008568:Memory / Q000187:drug effects; D043562:Receptors, G-Protein-Coupled / Q000378:metabolism; D011968:Receptors, Histamine / Q000378:metabolism; D000074040:Receptors, Histamine H4
chemical_list: D002800:Cholinesterase Inhibitors; C418607:HRH4 protein, human; D054828:Histamine H3 Antagonists; D007093:Imidazoles; D043562:Receptors, G-Protein-Coupled; D011968:Receptors, Histamine; D000074040:Receptors, Histamine H4