TY - JOUR
T1 - New N-arachidonoylserotonin analogues with potential "dual" mechanism of action against pain
AU - Ortar, Giorgio
AU - Cascio, Maria Grazia
AU - De Petrocellis, Luciano
AU - Morera, Enrico
AU - Rossi, Francesca
AU - Schiano-Moriello, Aniello
AU - Nalli, Marianna
AU - De Novellis, Vito
AU - Woodward, David F.
AU - Maione, Sabatino
AU - Di Marzo, Vincenzo
PY - 2007/12/27
Y1 - 2007/12/27
N2 - N-Arachidonoylserotonin (AA-5-HT, 1a) is an inhibitor of fatty acid amide hydrolase (FAAH) that acts also as an antagonist of transient receptor potential vanilloid-type 1 (TRPV1) channels and is analgesic in rodents. We modified the chemical structure of 1a with the aim of developing "hybrid" FAAH/TRPV1 blockers more potent than the parent compound or obtaining analogues with single activity at either of the two targets to study the mechanism of the analgesic action of 1a. Thirty-eight AA-5-HT analogues, containing a serotonin "head" bound to a variety of lipophilic moieties via amide, urea, or carbamate functionalities, were synthesized. Unlike 1a, most of the new compounds possessed activity at only one of the two considered targets. The amides 1b and 1c of α- and γ-linolenic acid, however, showed "hybrid" activity similar to 1a. The carbamate 3f (OMDM106), although unable to antagonize TRPV1 receptors, was the most potent FAAH inhibitor in this study (IC50 = 0.5 μM). Compounds 3f and 1m (OMDM129), which exhibited activity at only FAAH or TRPV1, respectively, were 10-fold less potent than 1a at preventing formalin-induced hyperalgesia in mice.
AB - N-Arachidonoylserotonin (AA-5-HT, 1a) is an inhibitor of fatty acid amide hydrolase (FAAH) that acts also as an antagonist of transient receptor potential vanilloid-type 1 (TRPV1) channels and is analgesic in rodents. We modified the chemical structure of 1a with the aim of developing "hybrid" FAAH/TRPV1 blockers more potent than the parent compound or obtaining analogues with single activity at either of the two targets to study the mechanism of the analgesic action of 1a. Thirty-eight AA-5-HT analogues, containing a serotonin "head" bound to a variety of lipophilic moieties via amide, urea, or carbamate functionalities, were synthesized. Unlike 1a, most of the new compounds possessed activity at only one of the two considered targets. The amides 1b and 1c of α- and γ-linolenic acid, however, showed "hybrid" activity similar to 1a. The carbamate 3f (OMDM106), although unable to antagonize TRPV1 receptors, was the most potent FAAH inhibitor in this study (IC50 = 0.5 μM). Compounds 3f and 1m (OMDM129), which exhibited activity at only FAAH or TRPV1, respectively, were 10-fold less potent than 1a at preventing formalin-induced hyperalgesia in mice.
UR - http://www.scopus.com/inward/record.url?scp=37349099085&partnerID=8YFLogxK
U2 - 10.1021/jm070678q
DO - 10.1021/jm070678q
M3 - Article
C2 - 18027904
AN - SCOPUS:37349099085
SN - 0022-2623
VL - 50
SP - 6554
EP - 6569
JO - Journal of Medicinal Chemistry
JF - Journal of Medicinal Chemistry
IS - 26
ER -