Thesis (Ph.D.) - Cairo University - Faculty of Pharmacy - Department of Pharmaceutical Chemistry

The present study involves the design and synthesis of compounds based on a tetrahydroisoquinoline scaffold linked via urea or amide group to a variety of hydrophobic substituents. Out of the 35 synthesized compounds, 30 compounds were screened for their ability to bind to the kappa opioid receptor in an attempt to come up with potential agents for the treatment of addiction. In addition, selected compounds were also tested against mu opioid receptors to evaluate their selectivity. Most of the tested compounds showed a good percentage of binding. In addition, the binding constant (Ki) for the compounds with highest percentage of binding (greater than 60%) was measured and compounds (S)-27c, (R)-27c, (R)-27d, (S)-27h, (R)-27h, (S)-27j, (S)-27k, (S)-27o, (S)-27b and (R)-27b were found to have the lowest Ki values that range from 0.8 to 9.3 oM. Molecular docking study was performed in the active site of both opioid receptor subtypes, mu and kappa, to predict the mode of binding which these compounds may adopt.Moreover, an in silico investigation based on a 500-ns molecular dynamics simulation was conducted using the selective agents, JDTic and Alvimopan, which have showed the most antagonistic activity against kappa and mu opioid receptors, respectively. This study could help in deciphering the molecular basis of kappa opioid receptor selectivity. Finally, we have performed a 100-ns molecular dynamic simulation using one of the most active compounds in our series, (R)-27d, with kappa opioid receptor, as a complementary work for the docking study, to elucidate the stability of the proposed binding mode of this compound

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