In vitro pharmacology at human histamine H3 receptors and brain access of non-imidazole alkylpiperidine derivatives

• Published in: Pharmacological research 2007-02, Vol.55 (2), p.111-116
• Main Authors: Bertoni, Simona, Flammini, Lisa, Manenti, Veronica, Ballabeni, Vigilio, Morini, Giovanni, Comini, Mara, Barocelli, Elisabetta
• Format: Article
• Language: English
• Subjects: Animals; Avoidance Learning - drug effects; Behavior, Animal - drug effects; Binding Sites; Cell Line, Tumor; Cerebral Cortex - drug effects; Cerebral Cortex - metabolism; Histamine Antagonists - chemistry; Histamine Antagonists - pharmacology; Humans; Imidazoles; Male; Molecular Structure; Piperidines - chemistry; Piperidines - pharmacology; Protein Binding; Radioligand Assay; Rats; Receptors, Histamine H3 - metabolism; Structure-Activity Relationship
• ISSN: 1043-6618
• DOI: 10.1016/j.phrs.2006.10.011

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.