Low Basicity as a Characteristic for Atypical Ligands of Serotonin Receptor 5-HT2

Abstract

Serotonin receptors are extensively examined by academic and industrial researchers, due to their vital roles, which they play in the organism and constituting therefore important drug targets. Up to very recently, it was assumed that the basic nitrogen in compound structure is a necessary component to make it active within this receptor system. Such nitrogen interacts in its protonated form with the aspartic acid from the third transmembrane helix (D3x32) forming a hydrogen bond tightly fitting the ligand in the protein binding site. However, there are several recent studies that report strong serotonin receptor affinity also for compounds without a basic moiety in their structures. In the study, we carried out a comprehensive in silico analysis of the low-basicity phenomenon of the selected serotonin receptor ligands. We focused on the crystallized representatives of the proteins of 5-HT1B, 5-HT2A, 5-HT2B, and 5-HT2C receptors, and examined the problem both from the ligand- and structure-based perspectives. The study was performed for the native proteins, and for D3x32A mutants. The investigation resulted in the determination of nonstandard structural requirements for activity towards serotonin receptors, which can be used in the design of new nonbasic ligands.

Environment-Sensitive Fluorescence of 7-Nitrobenz-2-oxa-1,3-diazol-4-yl (NBD)-Labeled Ligands for Serotonin Receptors

“…In this context, the chemical transformation of a basic primary amine into an amide deserves comment. Recent studies have shown that low basicity ligands for serotonin receptors, including the serotonin1A receptor, do exist [56,57], and this validates the design of our NBD-labeled probes using the reactive amine group. This could accoun for some loss in affinity of these ligands for the serotonin1A receptor (see later).…”

The Different Facets of Triclocarban: A Review

“…In this review, we will focus our attention on TCC, a small molecule also named 3,4,4′-trichlorocarbanilide that belongs to the class of diarylures or bis-arylureas. This interesting class of compounds has been recently reviewed by our research group as anticancer agents [ 6 ], and then, due to their multiple actions [ 7 , 8 , 9 , 10 , 11 ], they were also suggested for repositioning to antimicrobial agents and/or potential treatment for new pandemics, as COVID-19 [ 12 , 13 ]. TCC is a common ingredient in personal care products, especially dermal cleaning products such as antibacterial bar/Liquid soaps, body lotions, deodorants, detergents, medical disinfectants, aftershave soaps, hand sanitizers, toothpaste, handwash and mouthwash, body washes, cleansing lotions, baby teethers and wipes for its sanitizing properties and detergents [ 14 , 15 , 16 , 17 ].…”

“…In this review, we will focus our attention on TCC, a small molecule also named 3,4,4trichlorocarbanilide that belongs to the class of diarylures or bis-arylureas. This interesting class of compounds has been recently reviewed by our research group as anticancer agents [6], and then, due to their multiple actions [7][8][9][10][11], they were also suggested for Since its advent in 1957 [22], TCC has been produced and used on a large scale, and its consumption from personal care products in the United States reached 500,000-1,000,000 pounds per year [23]. The 2013-2014 National Health and Nutrition Examination Survey showed that 36.9% of the urine samples in the United States (U.S.) contained TCC [24].…”