N-substituted piperidinyl alkyl imidazoles:: Discovery of methimepip as a potent and selective histamine H3 receptor agonist

In this study, we continue our efforts toward the development of potent and highly selective histamine H-3 receptor agonists. We introduced various alkyl or aryl alkyl groups on the piperidine nitrogen of the known H-3/H-4 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 H-3 receptor (pK(i) = 9.0 and pEC(50) = 9.5) with a 2000-fold selectivity at the human H3 receptor over the human H-4 receptor and more than a 10000-fold selectivity over the human histamine H-1 and H-2 receptors. Methimepip was also very effective as an H-3 receptor agonist at the guinea pig ileum (pD(2) = 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.