Development of the first potential covalent inhibitors of anandamide cellular uptake.
On the basis of the chemical structures of two previously developed metabolically stable and relatively potent inhibitors of anandamide uptake, OMDM-1,2, two series of potential covalent inhibitors of anandamide cellular reuptake, which might be used for the molecular characterization of the protein(s) involved in the membrane transport of endocannabinoids, have been designed and synthesized. Most of the compounds inhibited uptake to a varied extent and in a generally enantio-sensitive manner when co-incubated with [(14)C]anandamide, but only three of them, the photoactivatable 1a (OMDM-37), 1b (OMDM-39), and 8(Lo395), also produced a significant inhibition of uptake following the preincubation only of the cells, and this effect was significantly enhanced following UV exposure only in the case of 8. None of the new compounds inhibited [(14)C]anandamide hydrolysis with IC(50) < 50 microM, except for 1b.
Endocannabinoid Research Group, Institute of Biomolecular Chemistry, Consiglio Nazionale delle Ricerche, via dei Campi Flegrei 34, 80078 Pozzuoli (Napoli), Italy.
Aniello
A
Schiano Moriello
Laurence
L
Balas
Alessia
A
Ligresti
Maria Grazia
MG
Cascio
Thierry
T
Durand
Enrico
E
Morera
Giorgio
G
Ortar
Vincenzo
V
Di Marzo
D000581:Amidohydrolases / Q000378:metabolism; D000818:Animals; D001095:Arachidonic Acids / Q000037:antagonists & inhibitors* / Q000138:chemical synthesis* / Q000378:metabolism / Q000494:pharmacology / Q000528:radiation effects; D001593:Benzyl Compounds / Q000138:chemical synthesis* / Q000494:pharmacology / Q000528:radiation effects; D001692:Biological Transport; D001921:Brain / Q000378:metabolism; D002460:Cell Line; D045744:Cell Line, Tumor; D002462:Cell Membrane / Q000378:metabolism; D063388:Endocannabinoids; D050612:Fatty Acid Transport Proteins / Q000378:metabolism; D006868:Hydrolysis; D066298:In Vitro Techniques; D053284:Polyunsaturated Alkamides; D051381:Rats; D013237:Stereoisomerism; D013329:Structure-Activity Relationship; D014466:Ultraviolet Rays; D000099252:Fatty Acid Amide Hydrolases
D000581:Amidohydrolases; D001095:Arachidonic Acids; D001593:Benzyl Compounds; D063388:Endocannabinoids; D050612:Fatty Acid Transport Proteins; D053284:Polyunsaturated Alkamides; D000099252:Fatty Acid Amide Hydrolases; C474344:OMDM-1 cpd; C474343:OMDM-2 cpd; C078814:anandamide