In this report, we describe the pharmacological profile of alkylpiperidine derivatives at human histamine H3 receptors and their ability to access central histamine H3 receptors in rodents. The three most attractive compounds exhibit high affinity and antagonistic potency (pKi ranging from 8.56 to 8.35) towards human histamine H3 receptors stably expressed in SK–N–MC cells and, in contrast to thioperamide, they show slightly greater affinity for human than for rodent H3 receptors. In ex vivo binding tests, they displayed a limited brain penetration since they displace [3H](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 H3 antagonists.