4-Amino-4-arylcyclohexanones and their derivatives, a novel class of analgesics. 1. Modification of the aryl ring

Lednicer, Daniel; Pf, VonVoigtlander; De, Emmert

doi:10.1021/jm00178a014

Cited by 20 publications

(13 citation statements)

References 2 publications

(3 reference statements)

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“…It was originally stated that BDPC/bromadol had 10,000 times the analgesic potency of morphine in animal studies [ 34 ] although a more recent study, comparing analgesic potency using a standard mouse hot plate assay where BDPC/bromadol was introduced by intraperitoneal injection, suggests that its analgesic potency may be lower, at around 500 times that of morphine and 2.9 times that of fentanyl [ 36 ]. BDPC/bromadol was the lead compound for a further series of 4-amino-4-arylcyclohexanone analogues and their derivatives prepared by the Upjohn team to provide structure activity relationship data [ 16 , 37 , 38 ]. None had analgesic properties greater than BDPC/bromadol, although a trans -chlorinated analogue showed similar potency as did an analogue where the phenethyl moiety was replaced with a cyclohex-3-ene moiety [ 37 ].…”

Section: Licit Drug Development: Evolution Of the N mentioning

confidence: 99%

The search for the “next” euphoric non-fentanil novel synthetic opioids on the illicit drugs market: current status and horizon scanning

et al. 2018

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PurposeA detailed review on the chemistry and pharmacology of non-fentanil novel synthetic opioid receptor agonists, particularly N-substituted benzamides and acetamides (known colloquially as U-drugs) and 4-aminocyclohexanols, developed at the Upjohn Company in the 1970s and 1980s is presented.MethodPeer-reviewed literature, patents, professional literature, data from international early warning systems and drug user fora discussion threads have been used to track their emergence as substances of abuse.ResultsIn terms of impact on drug markets, prevalence and harm, the most significant compound of this class to date has been U-47700 (trans-3,4-dichloro-N-[2-(dimethylamino)cyclohexyl]-N-methylbenzamide), reported by users to give short-lasting euphoric effects and a desire to re-dose. Since U-47700 was internationally controlled in 2017, a range of related compounds with similar chemical structures, adapted from the original patented compounds, have appeared on the illicit drugs market. Interest in a structurally unrelated opioid developed by the Upjohn Company and now known as BDPC/bromadol appears to be increasing and should be closely monitored.ConclusionsInternational early warning systems are an essential part of tracking emerging psychoactive substances and allow responsive action to be taken to facilitate the gathering of relevant data for detailed risk assessments. Pre-emptive research on the most likely compounds to emerge next, so providing drug metabolism and pharmacokinetic data to ensure that new substances are detected early in toxicological samples is recommended. As these compounds are chiral compounds and stereochemistry has a large effect on their potency, it is recommended that detection methods consider the determination of configuration.

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Section: Licit Drug Development: Evolution Of the N mentioning

confidence: 99%

The search for the “next” euphoric non-fentanil novel synthetic opioids on the illicit drugs market: current status and horizon scanning

et al. 2018

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“…This candidate active conformation was later dismissed by others [14] on account of its predictable high energy. Similarly, Lednicer and Von Voigtlander [15] showed, with the use of Dreiding models, that fentanyl and a potent la-selective Upjohn compound could assume conformatioris allowing superimposition of all salient structural features. They argued that for fentanyl such a conformation could be the pharmacologically active one but agreed that a rigorous conformational study would be needed to determine its energy requirements and its plausibility, since it was quite different from the solid and solution conformers.…”

Section: Introductionmentioning

confidence: 99%

Development of a conformational search strategy for flexible ligands: A study of the potent ?-selective opioid analgesic fentanyl

Cometta-Morini

Loew

1991

J Computer-Aided Mol Des

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An extensive conformational search of the potent opioid analgesic, fentanyl, was performed using the semiempirical quantum mechanical method AM1 and the CHARMm potential energy function. A combination of two procedures was used to search the conformational space for fentanyl, which included nested dihedral scans, geometry optimization and molecular dynamics simulation at different temperatures. In addition, the effect of a continuum solvent environment was taken into account by use of appropriate values for the dielectric constant in the CHARMm computations. The results of the conformational search allowed the determination of the probable conformation of fentanyl in polar and nonpolar solvents and of three candidate conformers for its bioactive form.

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“…7,8 As a starting point it was clear that, due to its size, compound 1 would lack key interactions within the binding pocket of both the NOP and MOP receptors and therefore would have only minimal receptor binding affinities (K i (NOP) = 1.5 μM; K i (MOP) = 1.7 μM). It was our strategy to utilize 1 as a core and its ketone moiety for functionalization.…”

Section: Introductionmentioning

confidence: 99%

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

Schunk¹,

Linz²,

Frormann³

et al. 2014

ACS Med. Chem. Lett.

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ABSTRACT:We report the discovery of spiro [cyclohexanepyrano[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. KEYWORDS: NOP receptor agonist, MOP receptor agonist F or decades, opioid peptide receptors have been targeted for the treatment of pain, and the present day opioids remain the most effective clinically used drugs for the treatment of moderate to severe acute and chronic pain. However, opioids also carry the risk of severe side effects such as respiratory depression, nausea, vomiting, and constipation, and their use may lead to physical dependence and tolerance.1 The nociceptin receptor and its endogenous ligand nociceptin/ orphanin FQ (N/OFQ), a 17-amino acid neuropeptide, have been described almost 20 years ago.2,3 Because of its partial homology to the three opioid peptide receptor subtypes mu opioid peptide (MOP), kappa opioid peptide (KOP), and delta opioid peptide (DOP) and its insensitivity to opioid agonists (e.g., morphine) and antagonists (e.g., naloxone), the receptor was initially termed "opioid-receptor-like 1" (ORL 1). More recently, however, it was renamed after its endogenous ligand to nociceptin/orphanin FQ peptide (NOP) receptor. Despite its structural and functional homology to opioid receptors, the NOP receptor is not an opioid peptide receptor from a pharmacological perspective and, as such, is considered a nonopioid member of the opioid peptide receptor family. 4 NOP and MOP receptor agonists modulate pain and nociception via distinct yet related targets. Addressing both mechanisms may constitute a novel approach for the development of innovative analgesics. Indeed, recent publications indicate that concurrent activation of NOP and MOP receptors may potentiate opiate analgesia and at the same time lead to an improved side effect profile. 5,6 We therefore aimed at identifying highly potent, small molecule NOP and MOP receptor agonists.This endeavor started with a literature-to-lead approach based on cyclohexanone 1, which has previously been reported by Lednicer et al. as representing a novel class of analgesics. 7,8 As a starting point it was clear that, due to its size, compound 1 would lack key interactions within the binding pocket of both the NOP and MOP receptors and therefore would have only minimal receptor binding affinities (K i (NOP) = 1.5 μM; K i (MOP) = 1.7 μM). It was our strategy to utilize 1 as a core and its ketone moiety for functionalization. Thus, fixing the 4-...

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4-Amino-4-arylcyclohexanones and their derivatives, a novel class of analgesics. 1. Modification of the aryl ring

Cited by 20 publications

References 2 publications

The search for the “next” euphoric non-fentanil novel synthetic opioids on the illicit drugs market: current status and horizon scanning

The search for the “next” euphoric non-fentanil novel synthetic opioids on the illicit drugs market: current status and horizon scanning

Development of a conformational search strategy for flexible ligands: A study of the potent ?-selective opioid analgesic fentanyl

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

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