Development and challenges in the discovery of 5-HT1A and 5-HT7 receptor ligands

Abstract

Serotonin (5-hydroxytryptamine) is a small molecule that acts both in the central and peripheral nervous system as a neurotransmitter and a hormone, respectively. Serotonin is synthesized via a multi-stage pathway beginning with l-tryptophan, which is converted by an enzyme called tryptophan hydroxylase into L-5-Hydroxytryptophan. It is well-known for its significance in the control of mood, anxiety, depression, and insomnia as well as in normal human functions such as sleep, sexual activity, and appetite. Thus, for medical chemists and pharmaceutical firms, serotonin is one of the most desirable targets. Among the seven different classes of serotonin receptors, the 5-HT_1A was one of the first discovered serotonin receptors, and the 5-HT₇ was the last addition to the serotonin receptor family. Both the classes were thoroughly examined. 5-HT_1A neurotransmission-related dysfunctions are linked to many psychological conditions such as anxiety, depression, and movement disorders. 5-HT₇ is a member of the cell surface receptor GPCR superfamily and is regulated by the serotonin neurotransmitter. It has been the focus of intensive research efforts since its discovery, which was prompted by its presence in functionally important regions of the brain. The thalamus and hypothalamus have the highest 5-HT₇ receptor densities. They are also found in the hippocampus and cortex at higher densities. Thermoregulation, circadian rhythm, learning and memory, and sleep are all associated with the 5-HT₇ receptor. It is also suspected that this receptor may be involved in the control of mood, indicating that it may be a beneficial target for depression treatment. Several differently structured molecules such as aminotetralins, ergolines, arylpiperazines, indolylalkylamines, aporphines, and aryloxyalkyl-amines are known to bind to 5-HT_1A and 5-HT₇ receptor sites. In brain serotonin receptors 5-HT_1A and 5-HT₇ are strongly co-expressed in regions involved in depression. However, their functional interaction has not been identified. An overview of the 5-HT_1A and 5-HT₇ receptor ligands belonging to different chemical groups is mentioned in this review.

Keywords: 5-HT(1A); 5-HT(7); Aminotetralins; Aporphines; Arylpiperazines; Ergolines Arylpiperazines; Indolylalkylamines.