The Trifluoromethyl Group as a Bioisosteric Replacement of the Aliphatic Nitro Group in CB₁ Receptor Positive Allosteric Modulators

Abstract

The first generation of CB 1 positive allosteric modulators (PAMs; e.g., ZCZ011) featured a 3-nitroalkyl-2-phenyl-indole structure. Although a small number of drugs include the nitro group, it is generally not regarded as being "drug-like", and this is particularly true for aliphatic nitro groups. There are very few case studies where an appropriate bioisostere replaced a nitro group that had a direct role in binding. This may be indicative of the difficulty of replicating its binding interactions. Herein we report the design and synthesis of ligands targeting the allosteric binding site on the CB 1 cannabinoid receptor, in which a CF 3 group successfully replaced the aliphatic NO 2 . In general, the CF 3 -bearing compounds were more potent than their NO 2 equivalents and also showed improved in vitro metabolic stability. The CF 3 -analogue (1) with the best balance of properties was selected for further

The Cannabinoid Receptor Type 1 Positive Allosteric Modulator ZCZ011 Attenuates Naloxone-Precipitated Diarrhea and Weight Loss in Oxycodone-Dependent Mice

“…ZCZ011 and related compounds (i.e., GAT211) show mixed allosteric agonistic and PAM properties, which have been termed CB 1 ago-PAMs (Kenakin, 2013). These compounds enhance the effects of CB 1 receptor orthosteric agonists (i.e., CP55,940, WIN55,212-2, or AEA) in a variety of functional assays, including [ 35 S] GTPγS-binding, β-arrestin recruitment and, inhibition of cAMP production, but also activate β-arrestin recruitment and inhibit cAMP production in the absence of CB 1 receptor orthosteric agonists (Ignatowska-Jankowska, Baillie, et al, 2015;Slivicki et al, 2017;Saleh et al, 2018;Tseng et al, 2019;Garai et al, 2021). Thus, additional studies (e.g., site directed mutagenesis) will be required to address the receptor mechanism(s) by which ZCZ011 ameliorates withdrawal signs in opioid-dependent mice.…”

“…Indeed, the CB 1 receptor PAMs ZCZ011 and GAT211 lack overt behavioral cannabimimetic effects, but produce antinociceptive effects in multiple rodent models of pain (Ignatowska-Jankowska, Baillie, et al, 2015;Slivicki et al, 2017Slivicki et al, , 2020Thapa et al, 2020) as well as reduce withdrawal signs in cannabinoiddependent mice (Trexler et al, 2019). These molecules are believed to bind at allosteric site(s) on the CB 1 receptor that results in a conformational change of the orthosteric site to enhance the binding and efficacy of endogenous cannabinoids and/or elicit allosteric agonist effects on their own (Dopart et al, 2018;Tseng et al, 2019), and may also be classified as a positive allosteric agonist (ago-PAMs) (Kenakin, 2013).…”

Photosensitized direct C–H fluorination and trifluoromethylation in organic synthesis

“…Due to the similar size to the hydrogen atom (r F = 1.47 Å, r H = 1.20 Å) [9,14], the fluorine atom is often used as a bioisostere for the hydrogen atom. Furthermore, the trifluoromethyl group was recently identified as a bioisostere for the nitro (NO 2 ) group, which is important due to the strong binding ability of the nitro group and the high reactivity, which is speculated to raise toxicity issues [15].…”

Synthesis and synthetic applications of (4-hydroxyphenyl)perfluoroalkylmethanols

“…The optimized condition depicted in Entry 7 was also applicable to 7c and 7d to furnish the corresponding products 8c and 8d in excellent yields (Entries 9 and 10), respectively. Transformation of the benzylic OH group to H was usually performed by way of the Bu3SnH-mediated radical reduction of the corresponding esters [29][30][31][32] or the corresponding halide [33]. However, it is quite interesting to note that the presence of a phenolic OH group at the p-position strongly facilitated this process just by the treatment with such a convenient and safe reagent as NaBH4.…”