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N-Morpholino- and N-diethyl-analogues of palmitoylethanolamide increase the sensitivity of transfected human vanilloid receptors to activation by anandamide without affecting fatty acid amidohydrolase activity
- Source :
- Bioorganic & Medicinal Chemistry. 11:817-825
- Publication Year :
- 2003
- Publisher :
- Elsevier BV, 2003.
-
Abstract
- The abilities of 19 analogues of palmitoylethanolamide and two analogues of oleoylethanolamide to affect the Ca(2+) influx into human embryonic kidney cells expressing the human vanilloid receptor (hVR1-HEK293 cells) in response to anandamide (AEA) have been investigated using a FLIPR assay and a bovine serum albumin-containing assay medium. Only palmitoylethanolamide produced any effect in the absence of AEA. The ability of palmitoylethanolamide to potentiate the response to AEA was retained when the N-CH(2)CH(2)OH group was replaced by N-CH(2)CH(2)Cl,whereas replacement with N-alkyl substituents [from -H up to -(CH(2))(12)CH(3)] resulted either in a reduction or in a complete loss of this activity. The tertiary amide N-(CH(2)CH(3))(2) (19) and N-morpholino (20) analogues of palmitoylethanolamide potentiated the response to 1 microM AEA to a greater degree than the parent compound, whereas the N-(CH(3))(2) analogue was inactive. 19 and 20 produced leftward shifts in the dose-response curve for AEA activation of Ca(2+) influx into hVR1-HEK293 cells. EC(50) values for AEA to produce Ca(2+) influx into hVR1-HEK293 cells were 1.1, 1.1, 0.54 and 0.36 microM in the presence of 0, 1, 3 and 10 microM 19, respectively. The corresponding values for 20 were 1.5, 1.3, 0.77 and 0.17 microM, respectively. The compounds did not affect the dose-response curves to capsaicin. The ability of oleoylethanolamide to potentiate AEA is retained by the N-CH(2)CH(3) and N-CH(CH(3))(2) analogues (22 and 23, respectively). 22 and 23 produced a small ( approximately 25%) inhibition of the binding of [(3)H]-CP55,940 and [(3)H]-WIN 55,212-2 to CB(1) and CB(2) receptors, respectively, expressed in CHO cells. The compounds inhibited the metabolism of 2 microM [(3)H]-AEA by rat brain fatty acid amidohydrolase with IC(50) values of 5.6 and 11 microM, respectively. In contrast, 19 and 20 were without effect on either binding to CB receptors or fatty acid amidohydrolase activity. Minor reductions in the accumulation of 10 microM [(3)H]-AEA into C6 glioma cells were seen at 10 microM concentrations of 19 and 20. It is concluded that 19 and 20 selectively enhance AEA effects upon VR1 receptors without potentially confounding effects upon CB receptors or fatty acid amidohydrolase activity.
- Subjects :
- Polyunsaturated Alkamides
Stereochemistry
Morpholines
Receptors, Drug
medicine.medical_treatment
Clinical Biochemistry
Pharmaceutical Science
Arachidonic Acids
Palmitic Acids
In Vitro Techniques
Kidney
Transfection
Biochemistry
Amidohydrolases
Radioligand Assay
chemistry.chemical_compound
Oleoylethanolamide
Receptor, Cannabinoid, CB1
Drug Discovery
Tumor Cells, Cultured
medicine
Animals
Humans
Molecular Biology
chemistry.chemical_classification
Palmitoylethanolamide
Amidohydrolase
Brain Neoplasms
Chemistry
Organic Chemistry
Fatty acid
Kidney metabolism
Biological activity
Glioma
Anandamide
Calcium Channel Blockers
Amides
Rats
Ethanolamines
Molecular Medicine
lipids (amino acids, peptides, and proteins)
Cannabinoid
Capsaicin
Endocannabinoids
Subjects
Details
- ISSN :
- 09680896
- Volume :
- 11
- Database :
- OpenAIRE
- Journal :
- Bioorganic & Medicinal Chemistry
- Accession number :
- edsair.doi.dedup.....ea8e382c519f89e9fbb04713fe6ead16