title: New N-arachidonoylserotonin analogues with potential "dual" mechanism of action against pain.
abstract: 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.
authors.affiliation: Dipartimento di Studi Farmaceutici, University of Rome La Sapienza, Italy.
authors.forename: Giorgio
authors.initials: G
authors.lastname: Ortar
authors.forename: Maria Grazia
authors.initials: MG
authors.lastname: Cascio
authors.forename: Luciano
authors.initials: L
authors.lastname: De Petrocellis
authors.forename: Enrico
authors.initials: E
authors.lastname: Morera
authors.forename: Francesca
authors.initials: F
authors.lastname: Rossi
authors.forename: Aniello
authors.initials: A
authors.lastname: Schiano-Moriello
authors.forename: Marianna
authors.initials: M
authors.lastname: Nalli
authors.forename: Vito
authors.initials: V
authors.lastname: de Novellis
authors.forename: David F
authors.initials: DF
authors.lastname: Woodward
authors.forename: Sabatino
authors.initials: S
authors.lastname: Maione
authors.forename: Vincenzo
authors.initials: V
authors.lastname: Di Marzo
mesh_terms: 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
chemical_list: 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