| The nociceptin/orphanin FQ opioid peptide (NOP) receptor with its unique biology continues to be an attractive molecular target for the development of ligands with potential therapeutic benefits. A ligand-based drug design approach was followed and a solution-phase parallel synthesis of target spirohydantoin piperidine analogues achieved. Additionally, azaspirobicyclo[3.2.1]octane and azaspirobicyco[3.3.1]nonane system based analogues were synthesized and evaluated biologically. SAR of substituting varied bulky groups on the "free nitrogen" of the hydantoin ring on ligand binding and intrinsic activity were explored. Although the compounds had no intrinsic activity, most were found to be allosteric potentiators of nociceptin-stimulated (∼EC80) calcium flux. Especially, compounds with bulky lipophilic fragments, with hydrogen bond acceptor and/or electron-withdrawing capability produced the greatest enhancement of nociceptin stimulation. For the first time, small-molecule, putative positive allosteric modulators of the NOP receptor are reported. |
