The 5-HT7R is involved in many physiological processes, i.e. the regulation of body temperature, circadian rhythm, learning and memory, as well as pathophysiological processes such as mood disorders, anxiety, schizophrenia and pain. None of the known 5-HT7R agonists qualify as perfect radioligand candidates, mainly due to their poor selectivity, metabolic stability or non-optimal ADME properties. Development of new ligands of 5-HT7R of the unique structure and properties. The compounds were concisely synthesized using van Leusen multi-component protocol and receptor affinity (5‑HT7, 1A, 2A, 6, and D2) was tested in radioligand binding assays. The intrinsic clearance was determined using human liver microsomes, whereas cytotoxicity was measured on HEK-293 and HepG2 cells. The pharmacokinetics of a lead compound was tested on CD-1 mice at 5 mg/kg dose (i.p.). The compound ability to reverse MK-801 induced impairment in novel object recognition test was conducted on Albino Swiss mice. Results: We have developed a series of 5-HT7R ligands, which are one of the very few examples of low-basicity aminergic receptor agonists. Lead compounds exhibited high affinity for the 5‑HT7R as well as high efficacy as agonists, excellent selectivity over related CNS targets, high metabolic stability and low toxicity. Docking to 5-HT7R homology models indicated a plausible binding mode which explain the unusually high selectivity. A rapid absorption to the blood, high blood-brain barrier permeation and a very high peak concentration in the brain were found for the lead compound. It was also found active in the NOR test. Because the compounds fulfill all the requirements needed for a PET radioligand a synthetic method which enables the incorporation of 11C isotope was developed. The obtained group of selective, low-basicity 5-HT7R receptor agonists has a great potential to be developed as pharmacological tools, radioligands or drug candidates. FINANCIAL SUPPORT: The study was partially supported by the Polish-Norwegian Research Programme operated by the National Centre for Research and Development under the Norwegian Financial Mechanism 2009–2014 in the frame of the Project PLATFORMex (Pol-Nor/198887/73/2013), www.platformex.eu.
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