Schunk Stefan, Linz Klaus, Frormann Sven, Hinze Claudia, Oberbörsch Stefan, Sundermann Bernd, Zemolka Saskia, Englberger Werner, Germann Tieno, Christoph Thomas, Kögel Babette-Y, Schröder Wolfgang, Harlfinger Stephanie, Saunders Derek, Kless Achim, Schick Hans, Sonnenschein Helmut
Departments of Medicinal Chemistry, Preclinical Drug Safety, Molecular Pharmacology, Pain Pharmacology, Pharmacokinetics, and Discovery Informatics, Global Drug Discovery, Grünenthal Innovation, Grünenthal GmbH , D-52099 Aachen, Germany.
ASCA GmbH Angewandte Synthesechemie Adlershof , Magnusstr. 11, 12489 Berlin, Germany.
ACS Med Chem Lett. 2014 Jun 24;5(8):851-6. doi: 10.1021/ml500116x. eCollection 2014 Aug 14.
We report the discovery of spiro[cyclohexane-pyrano[3,4-b]indole]-amines, as functional nociceptin/orphanin FQ peptide (NOP) and opioid receptor agonists with strong efficacy in preclinical models of acute and neuropathic pain. Utilizing 4-(dimethylamino)-4-phenylcyclo-hexanone 1 and tryptophol in an oxa-Pictet-Spengler reaction led to the formation of spiroether 2, representing a novel NOP and opioid peptide receptor agonistic chemotype. This finding initially stems from the systematic derivatization of 1, which resulted in alcohols 3-5, ethers 6 and 7, amines 8-10, 22-24, and 26-28, amides 11 and 25, and urea 12, many with low nanomolar binding affinities at the NOP and mu opioid peptide (MOP) receptors.
我们报告了螺[环己烷-吡喃并[3,4-b]吲哚]-胺的发现，其作为功能性孤啡肽/孤啡肽FQ肽（NOP）和阿片受体激动剂，在急性和神经性疼痛的临床前模型中具有强大疗效。利用4-(二甲基氨基)-4-苯基环己酮1和色醇进行氧杂-Pictet-Spengler反应，生成了螺醚2，它代表了一种新型的NOP和阿片肽受体激动剂化学类型。这一发现最初源于对1的系统衍生化，衍生化产物包括醇3-5、醚6和7、胺8-10、22-24以及26-28、酰胺11和25，还有脲12，其中许多在NOP和μ阿片肽（MOP）受体上具有低纳摩尔的结合亲和力。
