A critical review of both the synthesis approach and the receptor profile of the 8-chloro-1-(2′,4′-dichlorophenyl)-N-piperidin-1-yl-1,4,5,6-tetrahydrobenzo[6,7]cyclohepta[1,2-c]pyrazole-3-carboxamide and analogue derivatives

Paolo Lazzari, Rita Distinto, Ilaria Manca, Gemma Baillie, Gabriele Murineddu , Marilena Pira, Matteo Falzoi, Monica Sani, Paula Morales, Ruth Ross, Matteo Zanda, Nadine Jagerovic , Gerard Aime Pinna

Research output: Contribution to journalArticle

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Abstract

8-Chloro-1-(2′,4′-dichlorophenyl)-N-piperidin-1-yl-1,4,5,6-tetrahydrobenzo[6,7]cyclohepta[1,2-c]pyrazole-3-carboxamide 9a was discovered as potent and selective CB1 antagonist by part of our group few years ago. In particular it was reported to have an affinity towards the CB1 cannabinoid receptor (CB1R), expressed as Ki, of 0.00035 nM. Nevertheless significantly divergent data were reported for the same compound from other laboratories. To unequivocally define the receptor profile of 9a, we have critically reviewed both its synthesis approach and binding data. Here we report that, in contrast to our previously reported data, 9a showed a Ki value for CB1R in the order of nanomolar rather than of fentomolar range. The new determined receptor profile of 9a was also ascertained for analogue derivatives 9b-i, as well as for 12. Moreover, the structural features of the synthesized compounds necessary for CB1R were investigated. Amongst the novel series, effects on CB1R intrinsic activity was highlighted due to the substituents at the position 3 of the pyrazole ring of the 1,4,5,6-tetrahydrobenzo[6,7]cyclohepta[1,2-c]pyrazole scaffold.

Although the cannabinoid receptor profile of 9a was reviewed in this work, the relevance of this compound in CB1R antagonist based drug discovery is confirmed.
Original languageEnglish
Pages (from-to)194-208
Number of pages15
JournalEuropean Journal of Medicinal Chemistry
Volume121
Early online date6 May 2016
DOIs
Publication statusPublished - 4 Oct 2016

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Cannabinoid Receptor CB1
Derivatives
Cannabinoid Receptor Antagonists
Cannabinoid Receptors
Drug Discovery
Scaffolds
pyrazole

Keywords

  • cannabinoids
  • endocannabinoid system (ECS)
  • 8-chloro-1-(2’,4’-dichlorophenyl)-N-piperidin-1-yl-1,4,5,6-tetrahydrobenzo[6,7]cyclohepta[1,2-c]pyrazole-3-carboxamide
  • cannabinoid receptor binding assays
  • CB1 receptor ligands

Cite this

A critical review of both the synthesis approach and the receptor profile of the 8-chloro-1-(2′,4′-dichlorophenyl)-N-piperidin-1-yl-1,4,5,6-tetrahydrobenzo[6,7]cyclohepta[1,2-c]pyrazole-3-carboxamide and analogue derivatives. / Lazzari, Paolo; Distinto, Rita; Manca, Ilaria; Baillie, Gemma; Murineddu , Gabriele; Pira, Marilena; Falzoi, Matteo ; Sani, Monica; Morales, Paula; Ross, Ruth; Zanda, Matteo; Jagerovic , Nadine; Pinna, Gerard Aime.

In: European Journal of Medicinal Chemistry, Vol. 121, 04.10.2016, p. 194-208.

Research output: Contribution to journalArticle

Lazzari, Paolo ; Distinto, Rita ; Manca, Ilaria ; Baillie, Gemma ; Murineddu , Gabriele ; Pira, Marilena ; Falzoi, Matteo ; Sani, Monica ; Morales, Paula ; Ross, Ruth ; Zanda, Matteo ; Jagerovic , Nadine ; Pinna, Gerard Aime. / A critical review of both the synthesis approach and the receptor profile of the 8-chloro-1-(2′,4′-dichlorophenyl)-N-piperidin-1-yl-1,4,5,6-tetrahydrobenzo[6,7]cyclohepta[1,2-c]pyrazole-3-carboxamide and analogue derivatives. In: European Journal of Medicinal Chemistry. 2016 ; Vol. 121. pp. 194-208.
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abstract = "8-Chloro-1-(2′,4′-dichlorophenyl)-N-piperidin-1-yl-1,4,5,6-tetrahydrobenzo[6,7]cyclohepta[1,2-c]pyrazole-3-carboxamide 9a was discovered as potent and selective CB1 antagonist by part of our group few years ago. In particular it was reported to have an affinity towards the CB1 cannabinoid receptor (CB1R), expressed as Ki, of 0.00035 nM. Nevertheless significantly divergent data were reported for the same compound from other laboratories. To unequivocally define the receptor profile of 9a, we have critically reviewed both its synthesis approach and binding data. Here we report that, in contrast to our previously reported data, 9a showed a Ki value for CB1R in the order of nanomolar rather than of fentomolar range. The new determined receptor profile of 9a was also ascertained for analogue derivatives 9b-i, as well as for 12. Moreover, the structural features of the synthesized compounds necessary for CB1R were investigated. Amongst the novel series, effects on CB1R intrinsic activity was highlighted due to the substituents at the position 3 of the pyrazole ring of the 1,4,5,6-tetrahydrobenzo[6,7]cyclohepta[1,2-c]pyrazole scaffold.Although the cannabinoid receptor profile of 9a was reviewed in this work, the relevance of this compound in CB1R antagonist based drug discovery is confirmed.",
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T1 - A critical review of both the synthesis approach and the receptor profile of the 8-chloro-1-(2′,4′-dichlorophenyl)-N-piperidin-1-yl-1,4,5,6-tetrahydrobenzo[6,7]cyclohepta[1,2-c]pyrazole-3-carboxamide and analogue derivatives

AU - Lazzari, Paolo

AU - Distinto, Rita

AU - Manca, Ilaria

AU - Baillie, Gemma

AU - Murineddu , Gabriele

AU - Pira, Marilena

AU - Falzoi, Matteo

AU - Sani, Monica

AU - Morales, Paula

AU - Ross, Ruth

AU - Zanda, Matteo

AU - Jagerovic , Nadine

AU - Pinna, Gerard Aime

N1 - We thank European Commission (project “PET BRAIN: Mapping the brain with PET radiolabeled cannabinoid CB1 ligands”; FP7-People-2009-IAPP; Grant Agreement N.25142).

PY - 2016/10/4

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N2 - 8-Chloro-1-(2′,4′-dichlorophenyl)-N-piperidin-1-yl-1,4,5,6-tetrahydrobenzo[6,7]cyclohepta[1,2-c]pyrazole-3-carboxamide 9a was discovered as potent and selective CB1 antagonist by part of our group few years ago. In particular it was reported to have an affinity towards the CB1 cannabinoid receptor (CB1R), expressed as Ki, of 0.00035 nM. Nevertheless significantly divergent data were reported for the same compound from other laboratories. To unequivocally define the receptor profile of 9a, we have critically reviewed both its synthesis approach and binding data. Here we report that, in contrast to our previously reported data, 9a showed a Ki value for CB1R in the order of nanomolar rather than of fentomolar range. The new determined receptor profile of 9a was also ascertained for analogue derivatives 9b-i, as well as for 12. Moreover, the structural features of the synthesized compounds necessary for CB1R were investigated. Amongst the novel series, effects on CB1R intrinsic activity was highlighted due to the substituents at the position 3 of the pyrazole ring of the 1,4,5,6-tetrahydrobenzo[6,7]cyclohepta[1,2-c]pyrazole scaffold.Although the cannabinoid receptor profile of 9a was reviewed in this work, the relevance of this compound in CB1R antagonist based drug discovery is confirmed.

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KW - cannabinoid receptor binding assays

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JO - European Journal of Medicinal Chemistry

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SN - 0223-5234

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