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Novel Fubinaca/Rimonabant hybrids as endocannabinoid system modulators

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Abstract

The discovery of novel modulators of the cannabinoid system is a current topic in medicinal chemistry. In this paper, we report nine novel carboxamides designed as hybrids of Fubinaca family compounds and Rimonabant. These hybrids were obtained by linking the 1-benzyl-2,5-dichloroindazole-3-carboxylic acid to different amino acids bearing a hydrophobic side chain and three different C-terminus. The new chemical entities were tested in vitro to evaluate their bioactivity by means of receptor binding assays and [35S]GTPγS stimulation assays to reveal their affinity and potency. We found that all compounds were able to bind to the cannabinoid receptors in the low nanomolar range with a marked selectivity towards the CB1 cannabinoid receptor. Some of them are full agonists, whereas the others act as partial agonists. These molecules could be potentially used as anti-obesity agents, antiemetic and analgesics.

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Fig. 1
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Abbreviations

MCT:

Monocarboxylate transporter

MPC:

Mitochondrial pyruvate carrier

CB:

Cannabinoid receptor

SC:

Synthetic cannabinoid

SAR:

Structure activity relationships

EDC·HCl:

N′-Ethylcarbodiimide hydrochloride

HOBt:

Hydroxybenzotriazole

NMM:

N-Methylmorpholine

LRMS:

Low resolution mass spectrometry

1H-NMR:

Proton nuclear magnetic resonance

13C-NMR:

Carbon nuclear magnetic resonance

RP-HPLC:

Reverse phase high performance liquid chromatography

DMF:

Dimethylformamide

THF:

Tetrahydrofurane

TFA:

Trifluoroacetic acid

DCM:

Dichloromethane

DMSO:

Dimethyl sulfoxide

BSA:

Bovine serum albumin

EGTA:

Ethylene glycol-bis(2-aminoethylether)-N,N,N′,N′-tetraacetic acid

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Authors and Affiliations

  1. Department of Pharmacy, “G. d’Annunzio” University of Chieti-Pescara, Via dei Vestini 31, 66100, Chieti, Italy

    Azzurra Stefanucci, Giorgia Macedonio & Adriano Mollica

  2. Institute of Biochemistry, Biological Research Centre of the Hungarian Academy of Sciences, Temesvári krt. 62, Szeged, 6726, Hungary

    Szabolcs Dvorácskó & Csaba Tömböly

Authors
  1. Azzurra Stefanucci
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  2. Giorgia Macedonio
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  3. Szabolcs Dvorácskó
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  4. Csaba Tömböly
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  5. Adriano Mollica
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Corresponding authors

Correspondence to Csaba Tömböly or Adriano Mollica.

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The authors declare that no competing interests exist.

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This article does not contain any studies with human participants or animals performed by any of the authors.

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Handling Editor: V. Soloshonok.

This paper is based on the European patent with number EP18170728, to be used for priority declarations deposited in data May 4th, 2018 by the same authors, with the approval of all the inventors.

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Stefanucci, A., Macedonio, G., Dvorácskó, S. et al. Novel Fubinaca/Rimonabant hybrids as endocannabinoid system modulators. Amino Acids 50, 1595–1605 (2018). https://doi.org/10.1007/s00726-018-2636-1

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  • DOI: https://doi.org/10.1007/s00726-018-2636-1

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