Discovery of histamine H3 receptor antagonistic property of simple imidazole-free derivatives:: Preliminary pharmacological investigation

The histamine H-3 receptor subtype negatively modulates the release of various neurotransmitters such as histamine, glutamate, norepinephrine, acetylcholine and many others mainly in the CNS and H-3 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 H-3 receptor antagonists, currently indicated as a promising class of H-3 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 H-3 receptors. The imidazole-free derivatives possessed moderate to pronounced antagonistic potency at guinea-pig ileal H-3 receptor consistent with binding affinity at rat brain H-3 receptors and showed a favourable receptor selectivity profile. For the compound 5, with the highest affinity at rat H-3 receptors, comparable values were calculated in binding (pK(i) = 8.35) and functional (pA(2) = 8.22) assays in SK-N-MC cells stably expressing human H-3 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. (c) 2005 Elsevier Ltd. All rights reserved.