Indol-3-ylcycloalkyl Ketones: Effects of N1 Substituted Indole Side Chain Variations on CB₂ Cannabinoid Receptor Activity

Abstract

Several 3-acylindoles with high affinity for the CB(2) cannabinoid receptor and selectivity over the CB(1) receptor have been prepared. A variety of 3-acyl substituents were investigated, and the tetramethylcyclopropyl group was found to lead to high affinity CB(2) agonists (5, 16). Substitution at the N1-indole position was then examined. A series of aminoalkylindoles was prepared and several substituted aminoethyl derivatives were active (23-27, 5) at the CB(2) receptor. A study of N1 nonaromatic side chain variants provided potent agonists at the CB(2) receptor (16, 35-41, 44-47, 49-54, and 57-58). Several polar side chains (alcohols, oxazolidinone) were well-tolerated for CB(2) receptor activity (41, 50), while others (amide, acid) led to weaker or inactive compounds (55 and 56). N1 aromatic side chains also afforded several high affinity CB(2) receptor agonists (61, 63, 65, and 69) but were generally less potent in an in vitro CB(2) functional assay than were nonaromatic side chain analogues.

Identification and analytical properties of new synthetic cannabimimetics bearing 2,2,3,3-tetramethylcyclopropanecarbonyl moiety

“…These chemical shifts in 1 H and 13 C spectra of compound 16 are not characteristic for indole derivatives and differ substantially from the data for compounds 2 and 10 and from Refs. [20,26,27] data. We suggested that these could be rationalized by a mesomeric structure where positive charge is delocalized along a conjugation chain from indole N (resonance structure 16(N + )) to furan O (resonance structure 16(O + )) (Fig.…”

“…Further search has revealed packets with plant mixes and a packet with a powder which was later identified as (1-pentyl-1H-indol-3-yl)(2,2,3,3-tetramethylcyclopropyl)methanone (2) (our symbolic notation 'TMCP-018'). According to [20,21] the compound acts as a selective full agonist of the cannabinoid receptors CB 2 and CB 1 . Later smoking mixes containing 'TMCP-018' became extremely widely spread in Russia with a maximum in February 2012: only in Ekaterinburg there were 2-5 seizures daily.…”

“…Bioactivity and methods of synthesis of derivatives of 3-(2,2,3,3-tetramethylcyclopropanecarbonyl)indole compounds are described in the patents and the other literature [20][21][22][23]. According to these references 3-(2,2,3,3-tetramethylcyclopropanecarbonyl)indole derivatives possess strongly pronounced physiological activity similar to D 9 -tetrahydrocannabinol.…”

Pyrolysis of UR-144, a synthetic cannabinoid, augments an affinity to human CB₁ receptor and cannabimimetic effects in mice

“…Although UR-144 induces hypothermia and reduces locomotor activity in experimental animals (Wiley et al, 2013;Gatch and Forster, 2015;Banister et al, 2015), the effects are weaker than other typical synthetic cannabinoids such as JWH-018 and AM-2201 (Banister et al, 2015). It is possible that these phenomena are explained by receptor selectivity of UR-144, as its Ki values are 150 nM and 1.8 nM for CB 1 and CB 2 , respectively (Frost et al, 2010). On the other hand, UR-144 and its fluoro derivative XLR-11 [(1-(5-fluoropentyl)-1H-indol-3-yl)(2,2,3,3-tetramenthylcyclopropyl)methanone] contain a cyclopropyl ring (Fig.…”

The Synthesis and Pharmacological Evaluation of Adamantane-Derived Indoles: Cannabimimetic Drugs of Abuse

“…18,19 Additionally, the naphthalene group of JWH-018 is not mandatory for CB 1 binding, and many 1-alkylindoles containing alicyclic 3-acyl groups have been reported as cannabinoid ligands, including adamantane derivatives. 63 Indeed, analogues containing the N-(adamtan-1-yl)-1-alkyl-1H-indole-3-carboxamide core of SDB-001 are listed as prophetic structures in several patents by Makriyannis and colleagues, although SDB-001 itself is not described. 64−66 Pasquini and coworkers recently prepared several 5-arylated N-(adamtan-1-yl)-1-pentyl-1H-indole-3-carboxamides, however, these compounds generally functioned as selective CB 2 receptor inverse agonists rather than CB 1 receptor agonists.…”