TY - JOUR
T1 - Structure-affinity relationships and pharmacological characterization of new alkyl-resorcinol cannabinoid receptor ligands
T2 - Identification of a dual cannabinoid receptor/TRPA1 channel agonist
AU - Brizzi, Antonella
AU - Aiello, Francesca
AU - Marini, Pietro
AU - Cascio, Maria Grazia
AU - Corelli, Federico
AU - Brizzi, Vittorio
AU - De Petrocellis, Luciano
AU - Ligresti, Alessia
AU - Luongo, Livio
AU - Lamponi, Stefania
AU - Maione, Sabatino
AU - Pertwee, Roger G
AU - Di Marzo, Vincenzo
N1 - Copyright © 2014. Published by Elsevier Ltd.
PY - 2014/9/1
Y1 - 2014/9/1
N2 - 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.
AB - 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.
KW - cannabinoid ligands
KW - transient receptor potential ankyrin type-1 channel
KW - structure–affinity relationships
KW - alkyl-resorcinol derivatives
KW - anandamide
KW - endocannabinoids
KW - lipid modulators
U2 - 10.1016/j.bmc.2014.07.006
DO - 10.1016/j.bmc.2014.07.006
M3 - Article
C2 - 25065940
SN - 0140-525X
VL - 22
SP - 4770
EP - 4783
JO - Behavioral and Brain Sciences
JF - Behavioral and Brain Sciences
IS - 17
ER -