Anandamide prodrugs. 1. Water-soluble phosphate esters of arachidonylethanolamide and R-methanandamide.
Phosphate esters of arachidonylethanolamide (AEA) and R-methanandamide were synthesized and evaluated as water-soluble prodrugs. Various physicochemical properties (pK(a), partition coefficient, aqueous solubility) were determined for the synthesized phosphate esters. The chemical stability of phosphate esters was determined at pH 7.4. In vitro enzymatic hydrolysis rates were determined in 10% liver homogenate, and in a pure enzyme-containing (alkaline phosphatase) solution at pH 7.4. The intraocular pressure (IOP) lowering properties of R-methanandamide phosphate ester were tested on normotensive rabbits. The phosphate promoiety increased the aqueous solubility of the parent compounds by more than 16500-fold at pH 7.4. Phosphate esters were stable in buffer solutions, but rapidly hydrolyzed to their parent compounds in alkaline phosphatase solution (t(1/2)<<15 s) and liver homogenate (t(1/2)=8-9 min). The phosphate ester of R-methanandamide reduced IOP in rabbits. These results indicate that the phosphate esters of AEA and R-methanandamide are useful water-soluble prodrugs.
Juntunen
Juha
J
Department of Pharmaceutical Chemistry, University of Kuopio, PO Box 1627, FIN-70211, Kuopio, Finland
Huuskonen
Juhani
J
Laine
Krista
K
Niemi
Riku
R
Taipale
Hannu
H
Nevalainen
Tapio
T
Pate
David W
DW
Järvinen
Tomi
T
D000818:Animals; D001095:Arachidonic Acids / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D004355:Drug Stability; D063388:Endocannabinoids; D004798:Enzymes / Q000737:chemistry; D004952:Esters; D005260:Female; D006868:Hydrolysis; D007429:Intraocular Pressure / Q000187:drug effects; D008297:Male; D009883:Ophthalmic Solutions; D009943:Organophosphorus Compounds / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D053284:Polyunsaturated Alkamides; D011355:Prodrugs / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D011817:Rabbits; D012995:Solubility; D013237:Stereoisomerism; D014867:Water / Q000737:chemistry
D001095:Arachidonic Acids; D063388:Endocannabinoids; D004798:Enzymes; D004952:Esters; D009883:Ophthalmic Solutions; D009943:Organophosphorus Compounds; D053284:Polyunsaturated Alkamides; D011355:Prodrugs; D014867:Water; C088155:methanandamide; C078814:anandamide