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

Article abstract of DOI:10.1021/jm049475h

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 (pK _i = 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 H ₂ 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.