Drug design of 5-substituted-2-aminotetralins targeting the serotonin 5-HT7 receptor

• Online Access: http://hdl.handle.net/2047/D20287167

The neurotransmitter serotonin (5-hydroxytryptamine, 5HT) is found within both the periphery as well as the central nervous system (CNS). While the majority of 5-HT is found outside the CNS, it plays an important role centrally in influencing almost all human behaviors, as well as many psychiatric disorders. 5HT mediates its actions in the brain and periphery via 14 receptor types grouped into 7 families, all of which are G protein-coupled receptors (GPCRs), except for the 5HT₃ ion channel family. The Gαs coupled 5-HT₇ receptor is the most recent (1993) 5-HT receptor cloned. Unfortunately, there has been no crystal structure solved for 5-HT₇ leading to a lack of structural information. Lack of receptor structure, along with high transmembrane domain homology with the Gαi/o coupled 5-HT_1A GPCR, has made developing selective ligands for 5-HT₇ difficult, and as a result there are no approved pharmacotherapies that selectively target the 5-HT₇ receptor. Nevertheless, lurasodine is approved to treat schizophrenia and shows 5-HT₇ receptor antagonism, in addition to activity at several other GPCRs for serotonin and other neurotransmitters. Along with the therapeutic indication for schizophrenia, there is recent evidence from our lab and in the biomedical literature that 5HT₇ (as well as 5-HT_1A) GPCRs, are also involved in the pathophysiology and pharmacotherapy of cognitive dysfunction and stereotypy. Both cognitive dysfunction and stereotypy are associated with disorders such as autism spectrum disorder (ASD), Fragile X Syndrome (FXS) and substance use disorders and other compulsive behavioral disorders, yet there are few effective pharmacotherapies for any of these conditions.