The synthesis and H<sub>3</sub> receptor ligand of a new series of lactam derivatives are reported. The new compounds were evaluated in vitro in H<sub>3</sub> and H<sub>1</sub> receptor-binding assays. The structure-activity relationship led us to the promising derivative 2-methyl-7-(3-morpholinopropoxy)-3,4-dihydroisoquinolin-1(2H)-one (11). The compound with highest affinity and greatest selectivity were further profiled, In addition, compound 11 exerted dose-dependent anti-nociceptive effects in the formalin test. These characteristics suggested that the potent and selective compound 11 could be a potent candidate for pain treatment.