Synthesis, biological evaluation and structural analysis of novel peripherally active morphiceptin analogs

Synthesis, receptor binding studies, optical spectroscopic and in silico structural characterization of morphiceptin analogs with cis‐4‐amino‐L‐proline residues

“…Docked complexes of the active mu opioid receptor and compounds 2–4 are shown in Figure . All three molecules were found to localize in the binding cavity of the mu opioid receptor, and all three were bound in an extended conformation, slightly different from that observed earlier for F 2 Pro‐substituted morphiceptin analogs . Nevertheless, all three compounds are capable to form the contacts proposed earlier to be essential for the activation of this receptor .…”

“…All three molecules were found to localize in the binding cavity of the mu opioid receptor, and all three were bound in an extended conformation, slightly different from that observed earlier for F 2 Pro-substituted morphiceptin analogs [35]. Nevertheless, all three compounds are capable to form the contacts proposed earlier to be essential for the activation of this receptor [33,35]. Calculated inhibitory constants are in qualitative agreement with experimental data (Table 1).…”

Cyclic derivatives of morphiceptin possess anti-transit effect in the gastrointestinal tract and alleviate abdominal pain in mice

“…Literature shows that the effect of fluorine incorporation is hard to predict and strongly depends on its position in the derivative; the major effect is the alteration of acidity or basicity of the parent compound that impacts its pharmacological properties, bioavailability and receptor affinity [14]. Previously, fluorinated derivatives of morphiceptin were synthesized and evaluated by Adamska et al [15]. They assessed how the incorporation of fluorine in positions 2 or/and 4 by introduction of 4,4-difluoroproline (F 2 Pro) affects the receptor binding affinity of four fluorinated morphiceptin analogs.…”

“…Tested compounds varied by the affinity at MOP receptors: ligand 4 (Tyr-F 2 Pro-Phe-d-F 2 Pro-NH 2 ) presented the highest activity at MOP and relative low affinity at KOP receptors. It was concluded that the substitution of more hydrophobic derivative with F 2 Pro 2 instead of Pro 2 results in the formation of stronger ligand-receptor interactions [15].…”

Fluorine-Containing Prolines: Synthetic Strategies, Applications, and Opportunities

“…Indeed, with the development of novel synthetic methods, a repertoire of fluorinated prolines dramatically increased during the past two decades. It is impossible to consider in this Perspective each individual example in details, but the list of recent bioactive structures with a fragment of fluorinated proline along with a brief description of their application are outlined in Figure . − …”