Design and synthesis of a potential orexin receptor OX2R modulator with the use of in silico methods

Orexinergic nervous system is a complex of neurons playing a significant role in managing sleep cycle and food intake. Orexin neurons situated in the lateral hypothalamus produce orexin neuropeptides A and B, which interact with two orexin receptors in a broad range of neurons in the brain. A reduced production of these neuropeptides due to the loss of orexin neurons is the cause of a specific and rare disease narcolepsy, which is currently incurable. A significant milestone in terms of drug research and development against narcolepsy is a study of Takashi Nagaraha's scientific group (2015), which was the first one to synthesize a non-peptidic agonist of the orexin 2 receptor (OX2R) that has inspired further design of new drug candidates with an increased chance to reach the clinical practice. This Bachelor Thesis is focused on the design and organic synthesis of a novel OX2R agonist with a 2-deoxystreptamine substructure and follows the Nagahara's study using rational and computer-aided drug design. The theoretical part is dedicated to the literature review of this issue, the practical part focuses on the design of 11 ligands using in silico and medicinal chemistry methods. The organic synthesis was then proposed, based on a retrosynthetic analysis, for the final candidate with the optimal...