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.
Highlights
Serotonin receptors 5-HT6 (5-HT6 Rs) seem to be the most intriguing among the members of5-HTRs family and highly promising as a target for innovative therapy of CNS-diseases
Since the literature sources indicated passive transport of caffeine through biological membranes [24], the estimated better result of KMP-10 absorption in the Caco-2 model may be due to some up-take transporters, which are involved in KMP-10 transport through the Caco-2 cells. Results of both the parallel artificial membrane permeability assay (PAMPA) and Caco-2 assays are in good concordance with previously performed blood–brain barrier permeability simulation using QikProp from Schrödinger Suite software
Molecules 2019, 24, x that was placed almost exactly in the middle of the range predicted for permeable compounds (−0.3–1.2) [18]
Summary
5-HTRs family and highly promising as a target for innovative therapy of CNS (central nervous system)-diseases. Cloned in rat in 1993 [1,2], and in a human in 1996 [3], they represent the youngest 5-HTRs subtype with a unique distribution that is almost exclusively limited to brain areas, especially those responsible for memory and cognitive processes, i.e., the dorsal hippocampus, Molecules 2019, 24, x striatum and prefrontal cortex (PFC). In the PFC, which is critical to normal cognitive processes, e.g., attention,Serotonin impulsivity, planning, decision-making, memory, the learning receptors 5-HT6 Acid) interneurons, where they regulate neurotransmitter systems that affect the aforementioned youngest 5-HTRs subtype with a unique distribution that is almost exclusively limited to brain areas, processes especially [4,5]. R seem to processes, be pivotal successful treatment of those the responsible for of memory cognitive i.e.,for the the dorsal hippocampus, cognitive impairment.
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