http://www.cnr.it/ontology/cnr/individuo/prodotto/ID18747

New potent and selective inhibitors of anandamide reuptake with antispastic activity in a mouse model of multiple sclerosis (Articolo in rivista)

Type

Articolo in rivista (Classe)
Prodotto della ricerca (Classe)

Label

New potent and selective inhibitors of anandamide reuptake with antispastic activity in a mouse model of multiple sclerosis (Articolo in rivista) (literal)

Anno

2006-01-01T00:00:00+01:00 (literal)

Http://www.cnr.it/ontology/cnr/pubblicazioni.owl#doi

10.1038/sj.bjp.0706418 (literal)

Alternative label

Ligresti A; Cascio MG; Pryce G; Kulasegram S; Beletskaya I; De Petrocellis L; SahaB; Mahadevan A; Visentin C; Wiley JL; Baker D; Martin BR; Razdan RK; Di Marzo V (2006)
New potent and selective inhibitors of anandamide reuptake with antispastic activity in a mouse model of multiple sclerosis
in British journal of pharmacology
(literal)

Http://www.cnr.it/ontology/cnr/pubblicazioni.owl#autori

Ligresti A; Cascio MG; Pryce G; Kulasegram S; Beletskaya I; De Petrocellis L; SahaB; Mahadevan A; Visentin C; Wiley JL; Baker D; Martin BR; Razdan RK; Di Marzo V (literal)

Pagina inizio

83 (literal)

Pagina fine

91 (literal)

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ISI IF (2006) 3.825 Numero Citazioni 36 (literal)

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http://onlinelibrary.wiley.com/doi/10.1038/sj.bjp.0706418/abstract;jsessionid=AF2BF642395A9889EC7B31841391A102.d04t03 (literal)

Http://www.cnr.it/ontology/cnr/pubblicazioni.owl#numeroVolume

147 (literal)

Rivista

British journal of pharmacology (Rivista)

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9 (literal)

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1 (literal)

Http://www.cnr.it/ontology/cnr/pubblicazioni.owl#descrizioneSinteticaDelProdotto

studio sperimentale (literal)

Note

Scopu (literal)
ISI Web of Science (WOS) (literal)

Http://www.cnr.it/ontology/cnr/pubblicazioni.owl#affiliazioni

Endocannabinoid Research Group, Institute of Biomolecular Chemistry, C.N.R. Pozzuoli (Napoli), Institute of Neurology, University College, London Organix Inc., Woburn, MA, U.S.A. Department of Pharmacology & Toxicology, Medical College of Virginia, Virginia Commonwealth University Richmond, VA, U.S.A; Institute of Cybernetics, C.N.R. Pozzuoli (Napoli), Italy (literal)

Titolo

New potent and selective inhibitors of anandamide reuptake with antispastic activity in a mouse model of multiple sclerosis (literal)

Abstract

We previously reported that the compound O-2093 is a selective inhibitor of the reuptake of the endocannabinoid anandamide (AEA). We have now re-examined the activity of O-2093 in vivo and synthesized four structural analogs (O-2247, O-2248, O-3246, and O-3262), whose activity was assessed in: (a) binding assays carried out with membranes from cells overexpressing the human CB1 and CB2 receptors; (b) assays of transient receptor potential of the vanilloid type-1 (TRPV1) channel functional activity (measurement of [Ca2+]i); (c) [14C]AEA cellular uptake and hydrolysis assays in rat basophilic leukaemia (RBL-2H3) cells; (d) the mouse 'tetrad' tests (analgesia on a hot plate, immobility on a 'ring', rectal hypothermia and hypolocomotion in an open field); and (e) the limb spasticity test in chronic relapsing experimental allergic encephalomyelitis (CREAE) mice, a model of multiple sclerosis (MS). O-2093, either synthesized by us or commercially available, was inactive in the 'tetrad' up to a 20 mg kg-1 dose (i.v.). Like O-2093, the other four compounds exhibited low affinity in CB1 (Ki from 1.3 to >10 m) and CB2 binding assays (1.310 m), very low potency as fatty acid amide hydrolase (FAAH) inhibitors (IC50>25 m) and were inactive in the 'tetrad' up to a 30 mg kg-1 dose (i.v.). While O-2247 and O-2248 were poor inhibitors of [14C]AEA cellular uptake (IC50>40 m), O-3246 and O-3262 were quite potent in this assay. O-3246, which exhibits only a very subtle structural difference with O-2093, is the most potent inhibitor of AEA uptake reported in vitro under our experimental conditions (IC50=1.4 m) and is 12-fold more potent than O-2093. When injected intravenously O-3246 and O-3262, again like O-2093 and unlike O-2247 and O-2248, significantly inhibited limb spasticity in mice with CREAE. These data confirm the potential utility of selective AEA uptake inhibitors as anti-spasticity drugs in MS and, given the very subtle chemical differences between potent and weak inhibitors of uptake, support further the existence of a specific mechanism for this process. (literal)

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