Are the Hydantoin-1,3,5-triazine 5-HT6R Ligands a Hope to a Find New Procognitive and Anti-Obesity Drug? Considerations Based on Primary In Vivo Assays and ADME-Tox Profile In Vitro

Abstract

Though the 5-HT6 serotonin receptor is an important target giving both agonists and antagonists similar therapeutic potency in the treatment of topic CNS-diseases, no 5-HT6R ligand has reached the pharmaceutical market yet due to the too narrow chemical space of the known 5-HT6R agents and insufficient “drugability.” Recently, a new group of non-indole and non-sulfone hydantoin-triazine 5-HT6R ligands was found, where 3-((4-amino-6-(4-methylpiperazin-1-yl)-1,3,5-triazin-2-yl)methyl)-5-methyl-5-(naphthalen-2-yl)imidazolidine-2,4-dione (KMP-10) was the most active member. This study is focused on wider pharmacological and “druglikeness” characteristics for KMP-10. A computer-aided insight into molecular interactions with 5-HT6R has been performed. “Druglikeness” was examined using an eight-test panel in vitro, i.e., a parallel artificial membrane permeability assay (PAMPA), and Caco-2 permeability-, P-glycoprotein (Pgp) affinity-, plasma protein binding-, metabolic stability- and drug–drug interaction-assays, as well as mutagenicity- and HepG2-hepatotoxicity risk tests. Behavioral studies in vivo, i.e., elevated plus-maze (EPM) and novel object recognition (NOR) tests, were performed. Extended studies on the influence of KMP-10 on rats’ metabolism, including biochemical tests, were conducted in vivo. Results indicated significant anxiolytic and precognitive properties, as well as some anti-obesity properties in vivo, and it was found to satisfy the “druglikeness” profile in vitro for KMP-10. The compound seems to be a good lead-structure and candidate for wider pharmacological studies in search for new CNS-drugs acting via 5-HT6R.

Discovery of phenylselenoether-hydantoin hybrids as ABCB1 efflux pump modulating agents with cytotoxic and antiproliferative actions in resistant T-lymphoma

“…The in vitro evaluation of metabolic pathways was performed by 120 min incubation of compounds 5-7 at 37° C with mouse liver microsomes (MLMs) obtained from Sigma-Aldrich (St. Louis, MO, USA), according to the described previously protocols [48,49]. The LC/MS analyses with additional MS ion fragmentation of the products and substrates were performed to determine the most probable structures of metabolites.…”

“…The used CYP3A4 P450-Glo TM commercial assay was purchased from Promega (Madison, WI, USA). The influence of compounds on CYP3A4 activity was tested according to the manufacturer protocol and as described previously [48,49]. The bioluminescence signal was measured with a microplate reader EnSpire (Perkin Elmer, Waltham, MA, USA) in luminescence mode.…”

Molecular Insights into an Antibiotic Enhancer Action of New Morpholine-Containing 5-Arylideneimidazolones in the Fight against MDR Bacteria

“…The luminescent CYP3A4 P450-Glo™ assay was carried out according to a protocol described previously (Promega, Madison, WI, USA) [ 51 ]. The reference compound ketoconazole was obtained from Sigma-Aldrich.…”

Multitargeting the Action of 5-HT6 Serotonin Receptor Ligands by Additional Modulation of Kinases in the Search for a New Therapy for Alzheimer’s Disease: Can It Work from a Molecular Point of View?

“… The structural variety of 5-HT 6 R antagonists: ( a ) compounds 1 [ 23 , 24 ], 2 [ 25 ], 3 [ 26 , 27 , 28 , 29 ], 4 [ 30 , 31 , 32 ] and 5 [ 33 ] investigated in clinical trials; ( b ) compounds in the early stages of R&D: the non-indole and non-sulfone derivatives 6 [ 34 ], 7 [ 35 ], 8 [ 36 , 37 ], 9 [ 38 , 39 ], 10 [ 40 , 41 ]and 11 [ 42 ] and non-basic antagonists 12 [ 43 ] and 13 [ 43 , 44 ]. The affinity for 5-HT 6 R expressed with K i (nM).…”

“…Procognitive effects in the Novel Object Recognition (NOR) test for 8–10 . at the dose shown [ 36 , 37 , 38 , 39 , 40 , 41 ].…”