Astraea Therapeutics, LLC, 320 Logue Ave, Suite 142, Mountain View, CA 94043, USA.
Astraea Therapeutics, LLC, 320 Logue Ave, Suite 142, Mountain View, CA 94043, USA.
Bioorg Med Chem. 2023 Sep 7;92:117421. doi: 10.1016/j.bmc.2023.117421. Epub 2023 Jul 21.
The development of SAR around substituted N-piperidinyl indole-based nociceptin opioid receptor (NOP) ligands led to the discovery of a novel series of 2-substituted N-piperidinyl indoles that provide both selective NOP full agonists and bifunctional NOP full agonists-μ opioid (MOP) receptor partial agonists. 2-substituted N-piperidinyl indoles have improved potency at the NOP receptor and are NOP full agonists, compared to our previously reported 3-substituted N-piperidinyl indoles that are selective NOP partial agonists. SAR in this series of 2-substituted N-piperidinyl indoles shows that 2-substitution versus 3-substitution on the indole moiety affects their intrinsic activity and opioid receptor selectivity. Molecular docking of these 2-substituted N-piperidinyl indoles in an active-state NOP homology model and MOP receptor structures provides a rationale for the differences observed in the binding, functional profiles and selectivity of 2-substituted versus 3-substituted N-piperidinyl indoles.
取代的 N-哌啶基吲哚基孤啡肽(opioid)受体（NOP）配体周围 SAR 的发展导致了一系列新型 2-取代的 N-哌啶基吲哚的发现，这些化合物既提供了选择性 NOP 完全激动剂，又提供了双功能 NOP 完全激动剂-μ 阿片受体（MOP）受体部分激动剂。与我们之前报道的 3-取代的 N-哌啶基吲哚相比，2-取代的 N-哌啶基吲哚在 NOP 受体上具有更高的效力，并且是 NOP 完全激动剂，3-取代的 N-哌啶基吲哚是选择性 NOP 部分激动剂。该系列 2-取代的 N-哌啶基吲哚中的 SAR 表明，吲哚部分的 2-取代与 3-取代会影响它们的内在活性和阿片受体选择性。这些 2-取代的 N-哌啶基吲哚在活性 NOP 同源模型和 MOP 受体结构中的分子对接为观察到的 2-取代与 3-取代的 N-哌啶基吲哚在结合、功能特性和选择性方面的差异提供了依据。
