title: Discovery of histamine H3 receptor antagonistic property of simple imidazole-free derivatives: Preliminary pharmacological investigation.
abstract: The histamine H3 receptor subtype negatively modulates the release of various neurotransmitters such as histamine, glutamate, norepinephrine, acetylcholine and many others mainly in the CNS and H3 antagonists have been developed to treat central diseases characterized by neurotransmission disturbance such as schizophrenia, memory/learning and sleep disorders. In search for non-imidazole histamine H3 receptor antagonists, currently indicated as a promising class of H3 blockers, a series of simple alkylpiperidine derivatives has been studied to attain a preliminary pharmacological profile. The compounds were characterized in vitro in terms of binding affinity, antagonistic potency and selectivity at rodent H3 receptors. The imidazole-free derivatives possessed moderate to pronounced antagonistic potency at guinea-pig ileal H3 receptor consistent with binding affinity at rat brain H3 receptors and showed a favourable receptor selectivity profile. For the compound 5, with the highest affinity at rat H3 receptors, comparable values were calculated in binding (pKi = 8.35) and functional (pA2 = 8.22) assays in SK-N-MC cells stably expressing human H3 receptors. These findings indicate to extend the investigation to pharmacokinetic property and central effects to gain deeper knowledge on the pharmacological potential of this compound.
authors.affiliation: Dipartimento di Scienze Farmacologiche, Biologiche e Chimiche Applicate, Università di Parma, Parco Area delle Scienze 27/a, 43100 Parma, Italy. barocell@unipr.it
authors.forename: Elisabetta
authors.initials: E
authors.lastname: Barocelli
authors.forename: Vigilio
authors.initials: V
authors.lastname: Ballabeni
authors.forename: Veronica
authors.initials: V
authors.lastname: Manenti
authors.forename: Lisa
authors.initials: L
authors.lastname: Flammini
authors.forename: Simona
authors.initials: S
authors.lastname: Bertoni
authors.forename: Giovanni
authors.initials: G
authors.lastname: Morini
authors.forename: Mara
authors.initials: M
authors.lastname: Comini
authors.forename: Mariannina
authors.initials: M
authors.lastname: Impicciatore
mesh_terms: D000818:Animals; D002540:Cerebral Cortex / Q000378:metabolism; D004305:Dose-Response Relationship, Drug; D006168:Guinea Pigs; D006633:Histamine Antagonists / Q000737:chemistry / Q000378:metabolism / Q000494:pharmacology*; D007082:Ileum / Q000187:drug effects; D009130:Muscle, Smooth / Q000187:drug effects; D010880:Piperidines / Q000737:chemistry / Q000378:metabolism / Q000494:pharmacology*; D051381:Rats; D017208:Rats, Wistar; D018100:Receptors, Histamine H3 / Q000187:drug effects* / Q000235:genetics / Q000378:metabolism; D013329:Structure-Activity Relationship; D014162:Transfection
chemical_list: D006633:Histamine Antagonists; D010880:Piperidines; D018100:Receptors, Histamine H3