Galactosyl prodrug of palmitoylethanolamide: synthesis, stability, cell permeation and cytoprotective activity.
N-Palmitoylethanolamide (PEA) is emerging as a novel therapeutic agent in the treatment of neuropathic pain and neurodegenerative diseases. Unfortunately, PEA poorly reaches the central nervous system (CNS), after peripheral administration, since it is inactivated through intracellular hydrolysis by lipid amidases. Since prodrug approach is one of the most popular methods used to increase cell permeability, the aim of this paper consists in the synthesis of a new galactosyl prodrug of PEA, the palmitoylethanolamide-succinamyl-D-galactos-6'-yl ester (PEAGAL). Biological experiments both in neuroblastoma and in C6 glioma cells, together with quantitative analyses performed through a LC-MS-MS technique, demonstrate the better efficacy of PEAGAL compared to PEA and its higher cell permeation. Our results encourage further experiments in animal models of neuropathic pain and of neurological disorders and/or neurodegenerative diseases, in order to promote a more effective peripherally administrated derivative of PEA.
Department of Pharmacy, "Federico II" University of Naples, via Domenico Montesano 49, 80131 Naples, Italy. Electronic address: elvira.luongo@unina.it.
Elvira
E
Luongo
Department of Pharmacy, "Federico II" University of Naples, via Domenico Montesano 49, 80131 Naples, Italy.
Roberto
R
Russo
Department of Pharmacy, "Federico II" University of Naples, via Domenico Montesano 49, 80131 Naples, Italy.
Carmen
C
Avagliano
Department of Pharmacy, "Federico II" University of Naples, via Domenico Montesano 49, 80131 Naples, Italy.
Anna
A
Santoro
Department of Pharmacy, "Federico II" University of Naples, via Domenico Montesano 49, 80131 Naples, Italy.
Daniela
D
Melisi
Department of Pharmacy, "Federico II" University of Naples, via Domenico Montesano 49, 80131 Naples, Italy.
Nicola Salvatore
NS
Orefice
Department of Pharmacy, "Federico II" University of Naples, via Domenico Montesano 49, 80131 Naples, Italy.
Giuseppina Mattace
GM
Raso
Department of Pharmacy, "Federico II" University of Naples, via Domenico Montesano 49, 80131 Naples, Italy.
Rosaria
R
Meli
Department of Chemistry and Pharmacy, University of Sassari, via Muroni 23/a, 07100 Sassari, Italy.
Salvatore
S
Magliocca
Department of Chemistry and Pharmacy, University of Sassari, via Muroni 23/a, 07100 Sassari, Italy.
Maria
M
Nieddu
Department of Pharmacy, Faculty of Pharmacy, Universidade Federal do Ceará (UFC), Rua Capitão Francisco Pedro 1210, 60430-370 Fortaleza, CE, Brazil.
Gilvandete Maria Pinheiro
GM
Santiago
Department of Chemistry and Pharmacy, University of Sassari, via Muroni 23/a, 07100 Sassari, Italy.
Gianpiero
G
Boatto
Department of Pharmacy, "Federico II" University of Naples, via Domenico Montesano 49, 80131 Naples, Italy.
Antonio
A
Calignano
Department of Pharmacy, "Federico II" University of Naples, via Domenico Montesano 49, 80131 Naples, Italy.
Maria Grazia
MG
Rimoli
D000577:Amides; D000700:Analgesics / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology*; D001692:Biological Transport / Q000187:drug effects; D045744:Cell Line, Tumor; D002470:Cell Survival / Q000187:drug effects; D019610:Cytoprotection / Q000187:drug effects; D004355:Drug Stability; D004983:Ethanolamines / Q000378:metabolism; D005690:Galactose / Q000031:analogs & derivatives* / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology; D006801:Humans; D006863:Hydrogen-Ion Concentration; D018696:Neuroprotective Agents / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology*; D009573:Nitrites / Q000378:metabolism; D016627:Oxidopamine / Q000633:toxicity; D010168:Palmitates / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology*; D010169:Palmitic Acids / Q000378:metabolism; D010539:Permeability / Q000187:drug effects; D011355:Prodrugs / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology*
D000577:Amides; D000700:Analgesics; D004983:Ethanolamines; D018696:Neuroprotective Agents; D009573:Nitrites; D010168:Palmitates; D010169:Palmitic Acids; D011355:Prodrugs; C000596110:palmitoylethanolamide-succinamylgalactos-6'-yl ester; C005958:palmidrol; D016627:Oxidopamine; D005690:Galactose
Cell culture; Cytoprotection; Liquid chromatography; N-Palmitoylethanolamide; Permeability; Prodrugs