New N-arachidonoylserotonin analogues with potential "dual" mechanism of action against pain.
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 alpha- and gamma-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 microM). 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.
Ortar
Giorgio
G
Dipartimento di Studi Farmaceutici, University of Rome La Sapienza, Italy.
Cascio
Maria Grazia
MG
De Petrocellis
Luciano
L
Morera
Enrico
E
Rossi
Francesca
F
Schiano-Moriello
Aniello
A
Nalli
Marianna
M
de Novellis
Vito
V
Woodward
David F
DF
Maione
Sabatino
S
Di Marzo
Vincenzo
V
D000581:Amidohydrolases / Q000037:antagonists & inhibitors*; D000700:Analgesics / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D000818:Animals; D001095:Arachidonic Acids / Q000138:chemical synthesis* / Q000737:chemistry / Q000378:metabolism / Q000494:pharmacology; D001713:Biphenyl Compounds / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D001921:Brain / Q000201:enzymology; D002118:Calcium / Q000378:metabolism; D002219:Carbamates / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D002460:Cell Line; D063388:Endocannabinoids; D006801:Humans; D006868:Hydrolysis; D006930:Hyperalgesia / Q000188:drug therapy; D007211:Indoles / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D051379:Mice; D010146:Pain / Q000188:drug therapy*; D010147:Pain Measurement; D053284:Polyunsaturated Alkamides / Q000378:metabolism; D051381:Rats; D012701:Serotonin / Q000031:analogs & derivatives* / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology; D013329:Structure-Activity Relationship; D050916:TRPV Cation Channels / Q000037:antagonists & inhibitors*; D000099252:Fatty Acid Amide Hydrolases
D000581:Amidohydrolases; D000700:Analgesics; D001095:Arachidonic Acids; D001713:Biphenyl Compounds; D002118:Calcium; D002219:Carbamates; D063388:Endocannabinoids; D007211:Indoles; D053284:Polyunsaturated Alkamides; D012701:Serotonin; D050916:TRPV Cation Channels; D000099252:Fatty Acid Amide Hydrolases; C527720:(1,1'-biphenyl)-3-yl (2-(5-hydroxy-1H-indol-3-yl)ethyl)carbamate; C527719:N-(2-(5-hydroxy-1H-indol-3-yl)ethyl)-(1,1'-biphenyl)-3-acetamide; C494482:TRPV1 protein, human; C493922:Trpv1 protein, rat; C114007:arachidonoylserotonin; C078814:anandamide