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

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• 作者：Paolo Lazzari^a ; ^b ; ^c ; ^{paolo.lazzari@kemotech.it" class="auth_mail" title="E-mail the corresponding author} ; Rita Distinto^a ; ^b ; Ilaria Manca^a ; ^b ; Gemma Baillie^b ; ^d ; Gabriele Murineddu^e ; Marilena Pira^a ; ^b ; Matteo Falzoi^f ; Monica Sani^c ; ^g ; Paula Morales^h ; Ruth Ross^b ; ^d ; Matteo Zanda^b ; ^g ; Nadine Jagerovic^h ; Gé ; rard Aimè ; Pinna^e
• 关键词：cannabinoids ; Endocannabinoid system (ECS) ; 8-Chloro-1-(2&prime ; 4&prime ; -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
• 刊名：European Journal of Medicinal Chemistry
• 出版年：2016
• 出版时间：4 October 2016
• 年：2016
• 卷：121
• 期：Complete
• 页码：194-208
• 全文大小：1972 K

文摘

8-Chloro-1-(2′,4′-dichlorophenyl)-N-piperidin-1-yl-1,4,5,6-tetrahydrobenzo[6,7]cyclohepta[1,2-c]pyrazole-3-carboxamide boldFont">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 K_i, of 0.00035 nM. Nevertheless significantly divergent data were reported for the same compound from other laboratories. To unequivocally define the receptor profile of boldFont">9a, we have critically reviewed both its synthesis approach and binding data. Here we report that, in contrast to our previously reported data, boldFont">9a showed a K_i value for CB₁R in the order of nanomolar rather than of fentomolar range. The new determined receptor profile of boldFont">9a was also ascertained for analogue derivatives boldFont">9b-i, as well as for boldFont">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 boldFont">9a was reviewed in this work, the relevance of this compound in CB₁R antagonist based drug discovery is confirmed.