Pharmacophore Comparison and Development of Recently Discovered Long Chain Arylpiperazine and Sulfonamide Based 5-HT7 Ligands

Abstract

The serotonin system exerts its effects on the CNS and many peripheral systems. Of the 14 serotonin receptors, the 5-HT7 receptor is the most recently discovered. The 5-HT7 receptor has been shown to be involved in stress reduction, depression, and nociceptive control. Despite the 20 years since the discovery of 5-HT7R, there are still few truly selective ligands. Two of the common scaffolds for 5-HT7R ligands are long chain arylpiperazines (LCAPs) and sulfonamide containing compounds. This review focuses on recently developed (2014–2016) 5-HT7R ligands, their selectivity for the receptor, and suggests possible new pharmacophore models for these ligands.

Solvates of New Arylpiperazine Salicylamide Derivative-a Multi-Technique Approach to the Description of 5 HTR Ligand Structure and Interactions

“…The obtained results indicated that two different solvates were formed. Interestingly, the 15 Knowing that two different solvates, 1-MeOH and 1-EtOH, are formed, we focused on obtaining high-quality single crystals. In both cases, we obtained good enough crystals to perform scXRD experiments (Table S2).…”

“…The NMR experiments were performed using cross-polarization (CP), high-power decoupling, and magic-angle spinning (MAS) using a Bruker 4.0 mm HX CP/MAS probe with zirconia rotors driven by dry air. The spin rates of 8 kHz and 5 kHz for 13 C and 15 N NMR experiments were used, respectively. The Hartmann-Hahn conditions for 13 C and 15 N were matched using glycine 15-N.…”

“…To fully identify and characterize the ligand (1), various methods including singlecrystal X-ray diffraction (scXRD), powder X-ray diffraction (PXRD), solid-state nuclear magnetic resonance (ssNMR), and thermal analysis have been employed. The experimental studies have been additionally supplemented with ab initio calculations giving an insight into new solvates as well as 13 C and 15 N NMR shielding constants. Noteworthy is the ability of such a multitechnique approach to describe the molecular and crystal structures, particularly in the case of problematic crystals in scXRD experiments [16,17].…”

“…Unfortunately, there are no crystal structures of these two receptors determined to be up-to-date; therefore, only pharmacophore models can be used for structure-based ligand–receptor analysis. Based on pharmacophore models for 5-HT 1A [ 12 , 13 ] and 5-HT 7 [ 14 , 15 ] receptors, the effective arylpiperazine ligands have to contain a protonated nitrogen atom able to form charge-assisted hydrogen bonds, two or three hydrophobic/aromatic regions linking and two hydrogen bond acceptors. These molecular fragments of the arylpiperazine ligands are therefore expected to form the strongest interactions, also in the crystal.…”

<p>5-HT₇ Receptor Contributes to Proliferation, Migration and Invasion in NSCLC Cells</p>

“…Since it was discovered in 1993, there has been extensive research into its role in the central nervous system. 10 In addition to its wellestablished role in cognition, 11 circadian rhythms 12 and depression, 13 its involvement in various cancers has also been reported. [14][15][16][17][18] Although the 5-HT 7 receptor has been implicated in many lung-associated pathologic processes in rats 19,20 and guinea-pigs, 21,22 research on the 5-HT 7 receptor in human lungs is limited.…”