Histamine in the brain acts as a neurotransmitter to regulate diverse functions such as sleep-wake cycle. Recent studies have revealed the association of histaminergic dysfunction with neuropsychiatric disorders including narcolepsy and Alzheimer’s disease, emphasizing that the activation of brain histamine system have therapeutic potential to improve brain symptoms. Our previous study revealed the central role of a histamine metabolizing enzyme HNMT (histamine N-methyltransferase) in the regulation of brain histamine concentration, indicating the therapeutic potential of HNMT inhibitors for brain disorders associated with histamine dysfunction. However, specific HNMT inhibitors penetrating blood-brain barrier are not available until now. Therefore, in the present study, we aimed to find new HNMT inhibitors to stimulate histaminergic system and to ameliorate brain functions. First, we performed high throughput screening to find hit compounds from six thousand compounds. After structure-activity relationship study, we acquired potential candidates which could significantly increase brain histamine concentration. X-ray crystallography and pharmacokinetic analysis are now on-going. We hope these studies could further accelerate the development of HNMT inhibitors.