Microwave-assisted synthesis of purine derivatives with affinity for histamine 3 receptors

Histamine H3 receptors (H3Rs) are spread mainly in sympathetic and parasympathetic neurons of the CNS, regulating the release of various neurotransmitters such as histamine, dopamine, serotonin, acetylcholine and noradrenaline.1 As ligands at the receptor are known for modulating memory functions and arousal, the human H3R gained interest of the pharmaceutical industry due to its involvement in pathologies such as schizophrenia, Alzheimer's disease and sleep disorders. 2 This work describes the microwave-assisted synthesis of twelve novel histamine H3 receptor ligands. They display purine derivatives with rigidized aliphatic amines as warheads. The compounds were screened for H3R binding affinities in radioligand displacement assays and the most potent compounds were evaluated for H3R binding properties in vitro. Bipiperidine and morpholinepiperidine scaffold displayed higher affinity than a piperazine (Methyl, ethyl and cyclopentyl) or aminoethylmorpholine motif. The compounds can be starting points for novel, simply synthesized histamine H3 receptor ligands.