Novel tail and head group prostamide probes

Abstract

We report the design and synthesis of novel prostaglandin-ethanolamide (PGE2-EA) analogs containing head and tail group modifications to aid in the characterization of a putative prostamide receptor(s). Our synthetic approach utilizes Horner-Wadsworth-Emmons and Wittig reactions to construct the head and the tail moieties of the key PGE2 precursor, which leads to the final products through a peptide coupling, Swern oxidation and HF/pyridine assisted desilylation. The synthesized analogs were shown not to interact significantly with endocannabinoid proteins and recombinant EP1, EP3 and EP4 receptors and suggest a yet to be identified prostamide receptor as their site(s) of action.

(R)-N-(1-Methyl-2-hydroxyethyl)-13-(S)-methyl-arachidonamide (AMG315): A Novel Chiral Potent Endocannabinoid Ligand with Stability to Metabolizing Enzymes

“…In agreement with our earlier work on similar systems as well as prostaglandin analogues, this final Wittig olefination reaction is stereoselective and installs the C8C9 double bond with the Z stereochemistry. 6,17,22,23 Saponification of 20a and 20b (LiOH in THF/H 2 O) afforded acids 21a and 21b (94−96% yields) that were coupled with 2-(tert-butyldiphenylsilyloxy)ethanamine 23 to afford the silylated amide precursors 24a and 24b in excellent yields (95− 97%) by using the N,N′-carbonyldiimidazole-mediated amide coupling. 17,22 Deprotection of the tert-butyldimethylsilyl ether was carried out by using TBAF in THF and gave the enantiomeric (7R)-and (7S)-methyl anandamides 2e and 2f, respectively, in 85−88% yields.…”

“…1 H NMR (500 MHz, CDCl 3 ) δ 0.89 (t, J = 6.8 Hz, 3H, 20-H), 1.02 (d, J = 6.8 Hz, 3H, >CH−CH 3 ), 1. 23 (7S,5Z,8Z,11Z,14Z)-N-(2-Hydroxyethyl)-7-methyleicosa-5,8,11,14-tetraenamide (2f). The synthesis was carried out as described for 2b below, using 24b (30 mg, 0.05 mmol) and TBAF (0.07 mL, 1 M solution in THF) in dry THF (3 mL).…”

“…1 H NMR (600 MHz, CDCl 3 ) δ 0.89 (t, J = 6.7 Hz, 3H, 20-H), 1.02 (d, J = 6.6 Hz, 3H, CH-CH(CH 3 )−), 1.17 (d, J = 6.6 Hz, 3H, >N-CH(CH 3 )−), 1. 24 MS (EI): m/z (%): 375 (M + , 1), 374 (2), 312 (11), 284 (17), 257 (23), 244 (30), 171 (41), 57 (100). Exact mass (EI) calculated for C 24 H 41 NO 2 375.3137, found 375.3128.…”

The role of n-3 PUFA-derived fatty acid derivatives and their oxygenated metabolites in the modulation of inflammation

“…A simultaneous study by the same group showed that chemical modifications of PGE2-EA in both the head and tail group did not alter the biological interactions of the prostamide with the CB receptors and endocannabinoid enzymes. All chemically derived prostamides did not interact with prostaglandin EP receptors or other endocannabinoid related proteins, which is also true for PGE2-EA itself 121 . This indicates that these synthetic derivatives could play a role in the identification of novel prostamide receptors or prostamide-related proteins in the future.…”

Chiral Me-2-arachidonoyl Glycerols: The First Potent Endocannabinoid Glyceride Templates with Stability to COX-2

“…As such, it is challenging to modify the TC in such a way that it maintains (or preferably enhances) activity for CBRs while at the same time increases stability for oxidative enzymes. So far, the few reported AEA analogs with structural changes at the TC pharmacophore exhibit much lower CB1 affinities when compared to AEA, − Furthermore, despite multiple attempts over nearly 30 years, there has been no success toward developing 2-AG analogs with potent agonist properties for CBRs. − At best, previous analogs exhibited 10-fold lower ability to activate CB1 receptors when compared to 2-AG, while there are no reports for 2-AG analogs with activity on CB2.…”