Centro de Investigación Lilly, Avenida de la Industria 30, 28108-Alcobendas, Madrid, Spain.
J Med Chem. 2014 Apr 24;57(8):3418-29. doi: 10.1021/jm500117r. Epub 2014 Apr 11.
Nociceptin/OFQ (N/OFQ) is a 17 amino acid peptide that is the endogenous ligand for the ORL1/NOP receptor. Nociceptin appears to regulate a host of physiological functions such as biological reactions to stress, anxiety, mood, and drug abuse, in addition to feeding behaviors. To develop tools to study the function of nociceptin and NOP receptor, our research effort sought to identify orally available NOP antagonists. Our effort led to the discovery of a novel chemical series based on the dihydrospiro(piperidine-4,7'-thieno[2,3-c]pyran) scaffold. Herein we show that dihydrospiro(piperidine-4,7'-thieno[2,3-c]pyran)-derived compounds are potent NOP antagonists with high selectivity versus classical opioid receptors (μ, δ, and κ). Moreover, these compounds exhibit sufficient bioavailability to produce a high level of NOP receptor occupancy in the brain following oral administration in rats.
孤啡肽（N/OFQ）是一种由 17 个氨基酸组成的肽，是 ORL1/NOP 受体的内源性配体。孤啡肽似乎调节了一系列生理功能，如对压力、焦虑、情绪和药物滥用的生物反应，以及进食行为。为了开发研究孤啡肽和 NOP 受体功能的工具，我们的研究工作旨在确定口服可用的 NOP 拮抗剂。我们的努力导致发现了一种基于二氢螺（哌啶-4,7'-噻吩[2,3-c]吡喃）支架的新型化学系列。本文展示了二氢螺（哌啶-4,7'-噻吩[2,3-c]吡喃）衍生化合物是强效的 NOP 拮抗剂，对经典阿片受体（μ、δ 和 κ）具有高选择性。此外，这些化合物在大鼠口服给药后具有足够的生物利用度，可在大脑中产生高水平的 NOP 受体占有率。
