Highly potent and selective cannabinoid receptor 2 agonists: Initial hit optimization of an adamantyl hit series identified from high-through-put screening

Semi‐Rational Engineering of Toluene Dioxygenase from Pseudomonas putida F1 towards Oxyfunctionalization of Bicyclic Aromatics

“…As expected, the observed conversion for 2 (only 30%) was lower in comparison to 1 (100%), due to the larger size of substrate 2 . It is worth to mention that product 2 a is of great interest, considering its relevance as pharmaceutical synthon [22–24] . Thus, fostering 2 a production became an enticing task for this work.…”

“…It is worth to mention that product 2 a is of great interest, considering its relevance as pharmaceutical synthon. [22][23][24] Thus, fostering 2 a production became an enticing task for this work. By testing the single point TDO library with substrate 2 we identify the active site positions A223 and L321, and position F114, located at the putative ferredoxin binding site, [20] as positive hits favoring the total product formation (Figure S26).…”

Metabolic Profiling of a CB2 Agonist, AM9338, Using LC-MS and Microcoil-NMR: Identification of a Novel Dihydroxy Adamantyl Metabolite

“…It has been previously shown, that adamantane substitution is favorable for CB2 receptor binding affinity (Nettekoven et al, 2013) and for selectivity on the quinolone scaffold, most likely due to the favorable hydrophobic interactions between the adamantyl moiety and the CB2 binding pocket (Pasquini et al, 2008;Lamoureux and Artavia, 2010;Mallipeddi et al, 2017). In recently published CB2 crystal structure with the antagonist AM10257, adamantyl moiety was shown to extends toward helices II and III, establishing hydrophobic interactions with multiple phenyl alanine and histidine residues further stabilizing ligand-CB2 receptor complex (Li et al, 2019).…”

(3 + 2)-Annulation of 1,3-N,Si-tetraorganosilane reagents TsHNCH2SiBnR1R2 with arynes for efficient synthesis of 3-silaindolines

“…To demonstrate the potential of the resulting 3-silaindoline as a versatile platform skeleton in silicon-containing drug development, we carried out a series of comparative biological studies between sialindoline 10 and its carbon analog indoline 18 , a known cannabinoid receptor type 2 (CB 2 ) agonist targeting the central nervous system (CNS). 30 In the in vitro experiments, we used CHO cells stably expressing the CB 1 or CB 2 receptor as a model system to assess the ability of two compounds to inhibit the forskolin-induced increase in intracellular cAMP. Compared with 18 (EC 50 = 0.396 μM to CB 2 and EC 50 >50 μM to CB 1 ), 3-silalindoline 10 showed comparably good activity and still retained high selectivity toward CB 2 (EC 50 = 1.463 μM to CB 2 and EC 50 >50 μM to CB 1 ), indicating that carbon–silicon switching at the 3-position of indoline 18 did not affect its bioactivity.…”