ABSTRACT
In this report, we describe the pharmacological profile of alkylpiperidine derivatives at human histamine H(3) receptors and their ability to access central histamine H(3) receptors in rodents. The three most attractive compounds exhibit high affinity and antagonistic potency (pK(i) ranging from 8.56 to 8.35) towards human histamine H(3) receptors stably expressed in SK-N-MC cells and, in contrast to thioperamide, they show slightly greater affinity for human than for rodent H(3) receptors. In ex vivo binding tests, they displayed a limited brain penetration since they displace [(3)H](R)-alpha-methylhistamine from rat cerebral cortex after intraperitoneal administration at doses four times higher than thioperamide. Among these compounds, derivative 5 tends to counteract partially scopolamine-induced amnesia in passive avoidance task. On the whole, these findings contribute to the identification of the requirements of increasingly drug-like non-imidazole H(3) antagonists.
Subject(s)
Cerebral Cortex/drug effects , Histamine Antagonists/pharmacology , Piperidines/pharmacology , Receptors, Histamine H3/metabolism , Animals , Avoidance Learning/drug effects , Behavior, Animal/drug effects , Binding Sites , Cell Line, Tumor , Cerebral Cortex/metabolism , Histamine Antagonists/chemistry , Humans , Imidazoles , Male , Molecular Structure , Piperidines/chemistry , Protein Binding , Radioligand Assay , Rats , Structure-Activity RelationshipABSTRACT
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.
