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

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 (p K 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 )-α-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.