Application of genomics to drug design: the example of the histamine H3 receptor

The histamine H₃ receptor was characterized in the 1980s as an autoreceptor regulating histamine release in brain. Since then, selective drugs have been designed, many of them displaying a high potency in vivo, and used in many studies to delineate the implications of cerebral histaminergic systems in physiological functions such as arousal or cognitive functions. The recent cloning of the H₃ receptor, more than 15 years later, has allowed to start molecular studies that led to important findings for optimization of drug design. In agreement some ligands display distinct affinities for the recombinant rat and human H₃ receptors, a difference that we assign to two amino acids in the third transmembrane domain. In addition, H₃ autoreceptors present in the brain display high constitutive activity including in vivo. As a consequence, inverse agonists enhance histamine neuron activity and constitute a novel potential therapeutic approach to schizophrenia and Alzheimer’s disease.