Benzeneacetamide amines: structurally novel non-m.mu. opioids

Szmuszkovicz, Jacob; Pf, Von Voigtlander

doi:10.1021/jm00352a005

Cited by 165 publications

(119 citation statements)

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“…The preparation of U-47700 and other derivatives was disclosed by the Upjohn Company in the 1970s [7] followed by the recognition that U-47700 showed increased analgesic properties and morphine-like behavioural features in mice compared to morphine itself. [8,9] The presence of two chiral centres gives rise to a cis-and trans-racemic mixture with the trans-form being advertised for sale. Binding studies also revealed that U-47700 displayed an appreciable selectivity for the µ-opioid receptor over the κ−opioid receptor.…”

Section: Introductionmentioning

confidence: 99%

The first reported fatality associated with the synthetic opioid 3,4‐dichloro‐N‐[2‐(dimethylamino)cyclohexyl]‐N‐methylbenzamide (U‐47700) and implications for forensic analysis

Elliott¹,

Brandt

Smith³

2016

Drug Testing and Analysis

146

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Section: Introductionmentioning

confidence: 99%

The first reported fatality associated with the synthetic opioid 3,4‐dichloro‐N‐[2‐(dimethylamino)cyclohexyl]‐N‐methylbenzamide (U‐47700) and implications for forensic analysis

Elliott¹,

Brandt

Smith³

2016

Drug Testing and Analysis

146

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“…In contrast, nonopiates such as fentanyl 21 ( -selective agonist), U50,488, 22 and U69,593 23 ( -selective agonists) do not contain a traditional message and address. For these 2 ligand classes (the fentanyls and arylacetamides), docking studies predict a unique epitope that has minimal overlap with the opiate Serpentine model of the ␦ receptor.…”

Section: Introductionmentioning

confidence: 99%

Molecular recognition of opioid receptor ligands

Kane

Svensson

Ferguson

2006

AAPS J

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A BSTRACTThe cloning of the opioid receptors and subsequent use of recombinant DNA technology have led to many new insights into ligand binding. Instead of focusing on the structural features that lead to increased affi nity and selectivity, researchers are now able to focus on why these features are important. Site-directed mutagenesis and chimeric data have often been at the forefront in answering these questions. Herein, we survey pharmacophores of several opioid ligands in an effort to understand the structural requirements for ligand binding and selectivity. Models are presented and compared to illustrate key sites of recognition for both opiate and nonopiate ligands. The results indicate that different ligand classes may recognize different sites within the receptor, suggesting that multiple epitopes may exist for ligand binding and selectivity.

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“…1), was launched in Japan as an antipruritic for patients undergoing dialysis. 6,8,9) Although many arylacetamide derivatives such as U-50,488H 15,16) (Fig. 1) and U-69,593 17) were synthesized and developed as κ agonists, all of these derivatives were eliminated from clinical trials as not only analgesics but also as antipruritics because of their serious side effects like psychotomimetic and aversive reactions.…”

mentioning

confidence: 99%

Essential Structure of Opioid κ Receptor Agonist Nalfurafine for Binding to κ Receptor 1: Synthesis of Decahydroisoquinoline Derivatives and Their Pharmacologies

Nagase

Imaide

Yamada

et al. 2012

CHEMICAL & PHARMACEUTICAL BULLETIN

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On the basis of the three-dimensional pharmacophore model of opioid κ agonists, we simplified the structure of nalfurafine (selective κ agonist) to find the essential structural moieties for binding the opioid receptors, especially κ receptor type. As a result, we found that the trans-fused decahydroisoquinoline derivatives without a phenol ring bound the opioid receptor in micromolar order and that both the amide side chain and the nitrogen substituted by the cyclopropylmethyl group were indispensable moieties for eliciting the κ selectivity. The simple decahydroisoquinoline without amide side chain also bound the opioid receptor without receptor type selectivity, suggesting that the message-address concept would be applicable to even these simple derivatives. These findings that the simple decahydroisoquinoline derivatives showed the affinities for the opioid receptors, especially some of the compounds showed κ selectivity, are the first example in the opioid field.Key words opioid; κ receptor; decahydroisoquinoline; nalfurafine; three-dimensional pharmacophore model Three types of opioid receptors (μ, δ, κ) are now well established not only by pharmacological studies but also by molecular biological studies.1) Narcotic addiction is believed to be derived from the μ receptor type, and therefore δ and κ types are promising drug targets for analgesics without addiction. To obtain ideal analgesics without addiction and other side effects derived from the μ receptor, we have synthesized various kinds of naltrexone derivatives and have reported selective ligands for κ 2-9) and δ [10][11][12][13][14] receptors. Quite recently, one of our designed κ selective agonists, nalfurafine hydrochloride 2,3,6,8,9) Fig. 1), was launched in Japan as an antipruritic for patients undergoing dialysis. 6,8,9) Although many arylacetamide derivatives such as U-50,488H 15,16) (Fig. 1) and U-69,593 17) were synthesized and developed as κ agonists, all of these derivatives were eliminated from clinical trials as not only analgesics but also as antipruritics because of their serious side effects like psychotomimetic and aversive reactions. 18,19) In contrast, nalfurafine has neither aversive nor addictive effects. 20) Our interest in the differences in the pharmacological effects between nalfurafine and the arylacetamide derivatives led us to conduct a detailed structure activity relationship investigation of nalfurafine derivatives. From these studies, we developed the hypothesis that in the active conformation of nalfurafine (Fig. 2), the C-ring would assume the boat form, thereby elevating the amide side chain to bind the κ receptor. 4,5,21,22) Based on this hypothesis, we designed and synthesized KNT-63 with an oxabicyclo[2.2.2] octane skeleton ( Fig. 1), and confirmed its high affinity for the κ receptor. 5) We also proposed a new three-dimensional pharmacophore model applicable to some κ agonists with various chemotypes. 21,22) Our new pharmacophore model of κ agonists supported the proposed active conformation of nalfurafine and...

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Benzeneacetamide amines: structurally novel non-m.mu. opioids

Cited by 165 publications

References 1 publication

The first reported fatality associated with the synthetic opioid 3,4‐dichloro‐N‐[2‐(dimethylamino)cyclohexyl]‐N‐methylbenzamide (U‐47700) and implications for forensic analysis

The first reported fatality associated with the synthetic opioid 3,4‐dichloro‐N‐[2‐(dimethylamino)cyclohexyl]‐N‐methylbenzamide (U‐47700) and implications for forensic analysis

Molecular recognition of opioid receptor ligands

Essential Structure of Opioid κ Receptor Agonist Nalfurafine for Binding to κ Receptor 1: Synthesis of Decahydroisoquinoline Derivatives and Their Pharmacologies

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