Chemical update on the potential for serotonin 5-HT6 and 5-HT7 receptor agents in the treatment of Alzheimer’s disease

Perceiving the Concealed and Unreported Pharmacophoric Features of the 5-Hydroxytryptamine Receptor Using Balanced QSAR Analysis

“…Since the X-ray-resolved structure of 5-HT6 is not available, an appropriately validated and reported homology model built using a β2 receptor template (PDB ID: 4LDE) by Vanda et al [ 8 ] was used for molecular docking [ 6 , 7 ] in the present work. 4LDE (selected template) and 5-HT6 (modelled receptor) possess equivalent positions for the most conserved amino acid in each helix and motifs characteristic for class A GPCRs [ 6 , 7 , 8 ]. The sequences of 5-HT6 and 4LDE were retrieved from the UniProtKB/Swiss-Prot database [ 8 ].…”

“…An additional advantage associated with 5-HT6 is its restricted and exclusive occurrence within the CNS, which implies that compounds acting through this receptor could have minimal peripheral side effects [2,3,6,10,12]. Even though several molecules have been identified as promising ligands with high binding affinities for 5-HT6 (see Figure 1), none of them has cleared the clinical stages or been approved as a drug [1, [7][8][9][10]12]. Therefore, there is a need to develop a novel therapeutic agent with a better ADMET (absorption, distribution, metabolism, excretion, and toxicity) profile and the retention of a high binding affinity for 5-HT6.…”

“…[ 1 , 2 , 3 , 4 ], and are facing diverse health and social challenges. Though therapeutic agents are available for the treatment of these diseases, they lack the ability to reduce the continuous loss of cognitive function, as most of them target only the acetylcholine deficit [ 2 , 3 , 5 , 6 , 7 , 8 , 9 ]. Therefore, there is a need to develop a therapeutic agent with a different mechanism of action and bio-activity profile to support the existing drug space.…”

“…Therefore, there is a need to develop a therapeutic agent with a different mechanism of action and bio-activity profile to support the existing drug space. Recently, G-protein-coupled receptors (GPCRs), viz., the serotonergic system of serotonin (5-hydroxytryptamine) receptors, have received greater attention due to their vital role in signal transduction pathways and numerous neurological functions [ 2 , 4 , 7 , 8 , 9 , 10 ]. To add further, 5-hydroxytryptamine receptors (5-HT 1–7 ) play vital roles in many cognitive dysfunctions such as memory loss, reduced learning ability, etc.…”

“…An additional advantage associated with 5-HT6 is its restricted and exclusive occurrence within the CNS, which implies that compounds acting through this receptor could have minimal peripheral side effects [ 2 , 3 , 6 , 10 , 12 ]. Even though several molecules have been identified as promising ligands with high binding affinities for 5-HT6 (see Figure 1 ), none of them has cleared the clinical stages or been approved as a drug [ 1 , 7 , 8 , 9 , 10 , 12 ].…”