Discovery of Spiro[cyclohexane-dihydropyrano[3,4-b]indole]-amines as Potent NOP and Opioid Receptor Agonists

Autor:	Tieno Germann, Bernd Sundermann, Sven Frormann, Helmut Sonnenschein, Hans Schick, Werner Englberger, B.Y. Kögel, Derek Saunders, Achim Kless, Klaus Linz, Stefan Oberbörsch, Stephanie Harlfinger, Saskia Zemolka, Thomas Christoph, Claudia Hinze, Wolfgang P. Schröder, Stefan Schunk
Rok vydání:	2014
Předmět:	Indole test chemistry.chemical_classification Stereochemistry medicine.drug_class Organic Chemistry NOP Peptide Pharmacology Biochemistry chemistry.chemical_compound Nociceptin receptor chemistry Opioid receptor Drug Discovery Tryptophol medicine Receptor Opioid peptide
Zdroj:	ACS Medicinal Chemistry Letters. 5:851-856
ISSN:	1948-5875
DOI:	10.1021/ml500116x
Popis:	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.
Databáze:	OpenAIRE
Externí odkaz:	https://explore.openaire.eu/search/publication?articleId=doi_dedup___::c5fe90b0366ab101fe23bc576f011c77 https://doi.org/10.1021/ml500116x Zobrazit plný text záznamu