Structure-affinity relationships and pharmacological characterization of new alkyl-resorcinol cannabinoid receptor ligands

Identification of a dual cannabinoid receptor/TRPA1 channel agonist

Antonella Brizzi, Francesca Aiello, Pietro Marini, Maria Grazia Cascio, Federico Corelli, Vittorio Brizzi, Luciano De Petrocellis, Alessia Ligresti, Livio Luongo, Stefania Lamponi, Sabatino Maione, Roger G Pertwee, Vincenzo Di Marzo

Research output: Contribution to journalArticle

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Abstract

In our ongoing program aimed at deeply investigating the endocannabinoid system (ES), a set of new alkyl-resorcinol derivatives was prepared focusing on the nature and the importance of the carboxamide functionality. Binding studies on CB1 and CB2 receptors, monoacylglycerol lipase (MAGL) and fatty acid amide hydrolase (FAAH) showed that some of the newly developed compounds behaved as very potent cannabinoid receptor ligands (Ki in the nanomolar range) while, however, none of them was able to inhibit MAGL and/or FAAH. Derivative 11 was a potent CB1 and CB2 ligand, with Ki values similar to WIN 55,212, exhibiting a CB1 and CB2 agonist profile in vitro. In the formalin test of peripheral acute and inflammatory pain in mice, this compound showed a weak and delayed antinociceptive effect against the second phase of the nocifensive response, exhibiting, interestingly, a quite potent transient receptor potential ankyrin type-1 (TRPA1) channel agonist activity. Moreover, derivative 14, characterized by lower affinity but higher CB2 selectivity than 11, proved to behave as a weak CB2 competitive inverse agonist.

Original languageEnglish
Pages (from-to)4770-4783
Number of pages14
JournalBehavioral and Brain Sciences
Volume22
Issue number17
Early online date11 Jul 2014
DOIs
Publication statusPublished - 1 Sep 2014

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Monoacylglycerol Lipases
Ankyrins
Cannabinoid Receptors
Pharmacology
Cannabinoid Receptor CB2
Ligands
Cannabinoid Receptor CB1
Endocannabinoids
Acute Pain
Pain Measurement
resorcinol
fatty-acid amide hydrolase

Keywords

  • cannabinoid ligands
  • transient receptor potential ankyrin type-1 channel
  • structure–affinity relationships
  • alkyl-resorcinol derivatives
  • anandamide
  • endocannabinoids
  • lipid modulators

Cite this

Structure-affinity relationships and pharmacological characterization of new alkyl-resorcinol cannabinoid receptor ligands : Identification of a dual cannabinoid receptor/TRPA1 channel agonist. / Brizzi, Antonella; Aiello, Francesca; Marini, Pietro; Cascio, Maria Grazia; Corelli, Federico; Brizzi, Vittorio; De Petrocellis, Luciano; Ligresti, Alessia; Luongo, Livio; Lamponi, Stefania; Maione, Sabatino; Pertwee, Roger G; Di Marzo, Vincenzo.

In: Behavioral and Brain Sciences, Vol. 22, No. 17, 01.09.2014, p. 4770-4783.

Research output: Contribution to journalArticle

Brizzi, Antonella ; Aiello, Francesca ; Marini, Pietro ; Cascio, Maria Grazia ; Corelli, Federico ; Brizzi, Vittorio ; De Petrocellis, Luciano ; Ligresti, Alessia ; Luongo, Livio ; Lamponi, Stefania ; Maione, Sabatino ; Pertwee, Roger G ; Di Marzo, Vincenzo. / Structure-affinity relationships and pharmacological characterization of new alkyl-resorcinol cannabinoid receptor ligands : Identification of a dual cannabinoid receptor/TRPA1 channel agonist. In: Behavioral and Brain Sciences. 2014 ; Vol. 22, No. 17. pp. 4770-4783.
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