59529-21-4Relevant articles and documents
New-generation azaindole-adamantyl-derived synthetic cannabinoids
Longworth, Mitchell,Reekie, Tristan A.,Blakey, Karen,Boyd, Rochelle,Connor, Mark,Kassiou, Michael
, p. 350 - 365 (2019)
Purpose: This work reports the synthesis and pharmacological and analytical data for a new series of recently identified azaindole-adamantyl-derived synthetic cannabinoids (SCs). Methods: Each SC was synthesised using an efficient?and divergent synthesis, and assessed by electron ionisation mass spectrometry (EIMS). The cannabimimetic activity of each compound was conducted using a fluorometric imaging plate reader (FLIPR) assay. Results: The described EIMS method and retention time by gas chromatography were able to effectively differentiate each of the analogues regardless of the bicyclic core. For the first time in these SC structures, the bicyclic ring system was shown to have an impact on the cannabimimetic activities in the fluorometric assay of membrane potential. Analogues ranged from moderately potent at both CB1 and CB2 (e.g., AP4AIC EC50 = 160?nM and EC50 = 64?nM, respectively) to not active at either cannabinoid receptor (AP4AICA, AP5AICA, and APIC). Conclusions: Further investigation into receptor selectivity surrounding these bicyclic cores could prove useful for future therapeutic applications.
Exploring Stereochemical and Conformational Requirements at Cannabinoid Receptors for Synthetic Cannabinoids Related to SDB-006, 5F-SDB-006, CUMYL-PICA, and 5F-CUMYL-PICA
Ametovski, Adam,Macdonald, Christa,Manning, Jamie J.,Haneef, S. A. Syed,Santiago, Marina,Martin, Lewis,Sparkes, Eric,Reckers, Andrew,Gerona, Roy R.,Connor, Mark,Glass, Michelle,Banister, Samuel D.
, p. 3672 - 3682 (2020/11/18)
Synthetic cannabinoid receptor agonists (SCRAs) represent the most rapidly expanding class of new psychoactive substances (NPSs). Despite the prevalence and potency of recent chiral indole-3-carboxamide SCRAs, few pharmacological data are available regarding the enantiomeric bias of these NPSs toward human CB1 and CB2 receptors. A series of homochiral indole-3-carboxamides derived from (S)- and (R)-α-methylbenzylamine and featuring variation of the 1-alkyl substituent were prepared, pharmacologically evaluated, and compared to related achiral congeners derived from cumyl- and benzylamine. Competitive binding assays demonstrated that all analogues derived from either enantiomer of α-methylbenzylamine (14-17) showed affinities for CB1 (Ki = 47.9-813 nM) and CB2 (Ki = 47.9-347 nM) that were intermediate to that of the corresponding benzylic (10-13, CB1 Ki = 550 nM to >10 μM; CB2 Ki = 61.7 nM to >10 μM) and cumyl derivatives (6-9, CB1 Ki = 12.6-21.4 nM; CB2 Ki = 2.95-24.5 nM). In a fluorometric membrane potential assay, all α-methylbenzyl analogues (excluding 17) were potent, efficacious agonists of CB1 (EC50 = 32-464 nM; Emax = 89-104%) and low efficacy agonists of CB2 (EC50 = 54-500 nM; Emax = 52-77%), with comparable or greater potency than the benzyl analogues and much lower potency than the cumyl derivatives, consistent with binding trends. The relatively greater affinity and potency of (S)-14-17 compared to (R)-14-17 analogues at CB1 highlighted an enantiomeric bias for this series of SCRAs. Molecular dynamics simulations provided a conformational basis for the observed differences in agonist potency at CB1 pending benzylic substitution.
Tryptamine Synthesis by Iron Porphyrin Catalyzed C?H Functionalization of Indoles with Diazoacetonitrile
Hock, Katharina J.,Knorrscheidt, Anja,Hommelsheim, Renè,Ho, Junming,Weissenborn, Martin J.,Koenigs, Rene M.
supporting information, p. 3630 - 3634 (2019/02/13)
The functionalization of C?H bonds with non-precious metal catalysts is an important research area for the development of efficient and sustainable processes. Herein, we describe the development of iron porphyrin catalyzed reactions of diazoacetonitrile with N-heterocycles yielding important precursors of tryptamines, along with experimental mechanistic studies and proof-of-concept studies of an enzymatic process with YfeX enzyme. By using readily available FeTPPCl, we achieved the highly efficient C?H functionalization of indole and indazole heterocycles. These transformations feature mild reaction conditions, excellent yields with broad functional group tolerance, can be conducted on gram scale, and thus provide a unique streamlined access to tryptamines.
