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.
Palladium-Catalyzed Three-Component Regioselective Dehydrogenative Coupling of Indoles, 2-Methylbut-2-ene, and Carboxylic Acids
Guo, Rui-Li,Jia, Qiong,Wang, Meng-Yue,Wang, Yong-Qiang,Yang, Jin-Hui,Zhang, Xing-Long,Zhao, Bao-Yin
supporting information, p. 9574 - 9579 (2021/12/14)
Five-carbon (C5) structural units are the fundamental building blocks of many natural products. An unprecedented palladium-catalyzed three-component dehydrogenative cascade coupling of indoles, 2-methylbut-2-ene, and carboxylic acids has been developed. The approach enables the straightforward introduction of a C3′-bonded five-carbon structural unit with a tertiary alcohol quaternary carbon center into indoles. The protocol employs 2-methylbut-2-ene as the C5 source and is featured by a broad substrate scope, atom and step economies, and high chemo- and regioselectivies.
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.
Preparation of bivalent agonists for targeting the mu opioid and cannabinoid receptors
Dvorácskó, Szabolcs,Keresztes, Attila,Mollica, Adriano,Stefanucci, Azzurra,Macedonio, Giorgia,Pieretti, Stefano,Zádor, Ferenc,Walter, Fruzsina R.,Deli, Mária A.,Kékesi, Gabriella,Bánki, László,Tuboly, Gábor,Horváth, Gy?ngyi,T?mb?ly, Csaba
, p. 571 - 588 (2019/06/19)
In order to obtain novel pharmacological tools and to investigate a multitargeting analgesic strategy, the CB1 and CB2 cannabinoid receptor agonist JWH-018 was conjugated with the opiate analgesic oxycodone or with an enkephalin related tetrapeptide. The opioid and cannabinoid pharmacophores were coupled via spacers of different length and chemical structure. In vitro radioligand binding experiments confirmed that the resulting bivalent compounds bound both to the opioid and to the cannabinoid receptors with moderate to high affinity. The highest affinity bivalent derivatives 11 and 19 exhibited agonist properties in [35S]GTPγS binding assays. These compounds activated MOR and CB (11 mainly CB2, whereas 19 mainly CB1) receptor-mediated signaling, as it was revealed by experiments using receptor specific antagonists. In rats both 11 and 19 exhibited antiallodynic effect similar to the parent drugs in 20 μg dose at spinal level. These results support the strategy of multitargeting G-protein coupled receptors to develop lead compounds with antinociceptive properties.
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.
Iridium- and Rhodium-Catalyzed Directed C-H Heteroarylation of Benzaldehydes with Benziodoxolone Hypervalent Iodine Reagents
Grenet, Erwann,Waser, Jér?me
supporting information, p. 1473 - 1476 (2018/03/09)
The C-H heteroarylation of benzaldehydes with indoles and pyrroles was realized using the benziodoxolone hypervalent iodine reagents indole- and pyrroleBX. Functionalization of the aldehyde C-H bond using either an o-hydroxy or amino directing group and catalyzed by an iridium or a rhodium complex allowed the synthesis of salicyloylindoles and (2-sulfonamino)benzoylindoles, respectively, with good to excellent yields (74-98%). This new transformation could be carried out under mild conditions (rt to 40 °C) and tolerated a broad range of functionalities, such as ethers, halogens, carbonyls, or nitro groups.
Divergent dehydrogenative coupling of indolines with alcohols
Jiang, Xue,Tang, Weijun,Xue, Dong,Xiao, Jianliang,Wang, Chao
, p. 1831 - 1835 (2017/08/01)
The dehydrogenative coupling of indolines with alcohols catalyzed by an iridium complex has been achieved to afford both N- and C3-alkylated indoles selectively, by simply changing the addition time of a base additive. The iridacycle catalyst plays multiple roles in these reactions, which dehydrogenates both amines and alcohols and catalyzes the coupling reactions. Mechanistic studies reveal that a borrowing hydrogen-dehydrogenation process and a dehydrogenationborrowing hydrogen process are involved in N-alkylation and C3-alkylation reactions, respectively. The C3-alkylation reaction involves the direct coupling of two sp3 carbon centers.
The synthesis and pharmacological evaluation of adamantane-derived indoles: Cannabimimetic drugs of abuse
Banister, Samuel D.,Wilkinson, Shane M.,Longworth, Mitchell,Stuart, Jordyn,Apetz, Nadine,English, Katrina,Brooker, Lance,Goebel, Catrin,Hibbs, David E.,Glass, Michelle,Connor, Mark,McGregor, Iain S.,Kassiou, Michael
, p. 1081 - 1092 (2013/08/23)
Two novel adamantane derivatives, adamantan-1-yl(1-pentyl-1H-indol-3-yl) methanone (AB-001) and N-(adamtan-1-yl)-1-pentyl-1H-indole-3-carboxamide (SDB-001), were recently identified as cannabimimetic indoles of abuse. Conflicting anecdotal reports of the psychoactivity of AB-001 in humans, and a complete dearth of information about the bioactivity of SDB-001, prompted the preparation of AB-001, SDB-001, and several analogues intended to explore preliminary structure-activity relationships within this class. This study sought to elucidate which structural features of AB-001, SDB-001, and their analogues govern the cannabimimetic potency of these chemotypes in vitro and in vivo. All compounds showed similar full agonist profiles at CB1 (EC50 = 16-43 nM) and CB2 (EC50 = 29-216 nM) receptors in vitro using a FLIPR membrane potential assay, with the exception of SDB-002, which demonstrated partial agonist activity at CB2 receptors. The activity of AB-001, AB-002, and SDB-001 in rats was compared to that of Δ9-tetrahydrocannabinol (Δ9-THC) and cannabimimetic indole JWH-018 using biotelemetry. SDB-001 dose-dependently induced hypothermia and reduced heart rate (maximal dose 10 mg/kg) with potency comparable to that of Δ9-tetrahydrocannabinol (Δ9-THC, maximal dose 10 mg/kg), and lower than that of JWH-018 (maximal dose 3 mg/kg). Additionally, the changes in body temperature and heart rate affected by SDB-001 are of longer duration than those of Δ9-THC or JWH-018, suggesting a different pharmacokinetic profile. In contrast, AB-001, and its homologue, AB-002, did not produce significant hypothermic and bradycardic effects, even at relatively higher doses (up to 30 mg/kg), indicating greatly reduced potency compared to Δ9-THC, JWH-018, and SDB-001.
Novel indole and azaindole (pyrrolopyridine) cannabinoid (CB) receptor agonists: Design, synthesis, structure-activity relationships, physicochemical properties and biological activity
Blaazer, Antoni R.,Lange, Jos H.M.,Van Der Neut, Martina A.W.,Mulder, Arie,Den Boon, Femke S.,Werkman, Taco R.,Kruse, Chris G.,Wadman, Wytse J.
experimental part, p. 5086 - 5098 (2011/11/29)
The discovery, synthesis and structure-activity relationship (SAR) of a novel series of cannabinoid 1 (CB1) and cannabinoid 2 (CB 2) receptor ligands are reported. Based on the aminoalkylindole class of cannabinoid receptor agonists, a biphenyl moiety was introduced as novel lipophilic indole 3-acyl substituent in 11-16. Furthermore, the 3-carbonyl tether was replaced with a carboxamide linker in 17-20 and the azaindole (pyrrolopyridine) nucleus was designed as indole bioisostere with improved physicochemical properties in 21-25. Through these SAR efforts, several high affinity CB1/CB2 dual cannabinoid receptor ligands were identified. Indole-3-carboxamide 17 displayed single-digit nanomolar affinity and ～80 fold selectivity for CB1 over the CB2 receptor. The azaindoles displayed substantially improved physicochemical properties (lipophilicity; aqueous solubility). Azaindole 21 elicited potent cannabinoid activity. Cannabinoid receptor agonists 17 and 21 potently modulated excitatory synaptic transmission in an acute rat brain slice model of cannabinoid receptor-modulated neurotransmission.
Remarkable fast n-alkylation of azaheterocycles under microwave irradiation in dry media
Bogdal, Dariusz,Pielichowski, Jan,Jaskot, Krzysztof
, p. 715 - 722 (2007/10/03)
Under microwave irradiation a number of azaheterocycles (i.e., pyrrole, imidazole, pyrazole, indole, and carbazole) react remarkably fast with alkyl halides to give exclusively N-alkyl derivatives.
