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Discovery of a Potent Analgesic NOP and Opioid Receptor Agonist: Cebranopadol.

ABSTRACT: In a previous communication, our efforts leading from 1 to the identification of spiro[cyclohexane-dihydropyrano[3,4-b]indole]-amine 2a as analgesic NOP and opioid receptor agonist were disclosed and their favorable in vitro and in vivo pharmacological properties revealed. We herein report our efforts to further optimize lead 2a, toward trans-6'-fluoro-4',9'-dihydro-N,N-dimethyl-4-phenyl-spiro[cyclohexane-1,1'(3'H)-pyrano[3,4-b]indol]-4-amine (cebranopadol, 3a), which is currently in clinical development for the treatment of severe chronic nociceptive and neuropathic pain.

SUBMITTER: Schunk S

PROVIDER: S-EPMC4137374 | biostudies-literature | 2014 Aug

REPOSITORIES: biostudies-literature

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Discovery of a Potent Analgesic NOP and Opioid Receptor Agonist: Cebranopadol.

Schunk Stefan S Linz Klaus K Hinze Claudia C Frormann Sven S Oberbörsch Stefan S Sundermann Bernd B Zemolka Saskia S Englberger Werner W Germann Tieno T Christoph Thomas T Kögel Babette-Y BY Schröder Wolfgang W Harlfinger Stephanie S Saunders Derek D Kless Achim A Schick Hans H Sonnenschein Helmut H

ACS medicinal chemistry letters 20140624 8

In a previous communication, our efforts leading from 1 to the identification of spiro[cyclohexane-dihydropyrano[3,4-b]indole]-amine 2a as analgesic NOP and opioid receptor agonist were disclosed and their favorable in vitro and in vivo pharmacological properties revealed. We herein report our efforts to further optimize lead 2a, toward trans-6'-fluoro-4',9'-dihydro-N,N-dimethyl-4-phenyl-spiro[cyclohexane-1,1'(3'H)-pyrano[3,4-b]indol]-4-amine (cebranopadol, 3a), which is currently in clinical de ...[more]

PMID: 25147603

Similar Datasets

A diastereoselective synthesis of Cebranopadol, a novel analgesic showing NOP/mu mixed agonism.

Project description:A diastereoselective synthesis of the title compound as a single E diastereomer has been efficiently accomplished by assembling the featured pyrano-indole scaffold of the spiro[cyclohexane-dihydropyrano[3,4-b]-indole]-amine framework through an oxa-Pictet-Spengler reaction, promoted by a cheap and green Zeolite catalyst. Basic pharmacological experiments demonstrate that Cebranopadol acts as a mixed nociception/orphanin FQ (NOP) and mu (MOP) opioid receptor agonist useful for treatment of chronic pain.

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

Project description: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.

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Discovery of SHR9352: A Highly Potent G Protein-Biased μ-Opioid Receptor Agonist.

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Novel Mixed NOP/Opioid Receptor Peptide Agonists.

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A bifunctional nociceptin and mu opioid receptor agonist is analgesic without opioid side effects in nonhuman primates.

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Opioid receptor signaling, analgesic and side effects induced by a computationally designed pH-dependent agonist.

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