In this study, we continue our efforts toward the development of potent and highly selective histamine H3 receptor agonists. We introduced various alkyl or aryl alkyl groups on the piperidine nitrogen of the known H3/H4 agonist immepip and its analogues (1−3a). We observed that N-methyl-substituted immepip (methimepip) exhibits high affinity and agonist activity at the human histamine H3 receptor (pKi = 9.0 and pEC50 = 9.5) with a 2000-fold selectivity at the human H3 receptor over the human H4 receptor and more than a 10000-fold selectivity over the human histamine H1 and H2 receptors. Methimepip was also very effective as an H3 receptor agonist at the guinea pig ileum (pD2 = 8.26). Moreover, in vivo microdialysis (in rat brain) showed that methimepip reduces the basal level of brain histamine to about 25% after a 5 mg/kg intraperitoneal administration.