New-generation azaindole-adamantyl-derived synthetic cannabinoids

Abstract

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 CB 1 and CB 2 (e.g., AP4AIC EC 50 = 160 nM and EC 50 = 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. Keywords Synthetic cannabinoid • Azaindole • Adamantyl • CB 1 and CB 2 • APICA • Gas chromatography-mass spectrometry Electronic supplementary material The online version of this article (

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“…As part of the synthesis of 3‐carboxylate ( 28 ) and 3‐carboxamide ( 29 ) azaindoles (Scheme ), Longworth et al have suggested that the presence of an electron withdrawing pyridyl N‐atom in the azaindole core may hinder acylation at the C‐3 position of the azaindole ring. However, functionalization of the azaindole C‐3 position of 30 – 33 has been demonstrated to proceed smoothly, when treated with trifluoroacetic anhydride in the presence of aluminum chloride, to give SCRA intermediates 34 – 37 in moderate to excellent yields (63–95%) (Scheme ) …”

“…Synthesis of 3‐carboxylate ( 28 ) and carboxamide ( 29 ) azaindole SCRAs via C‐3 acylation of 1‐ N ‐pentyl azaindoles 30–33, in the presence of AlCl 3 and trifluoroacetic anhydride, to give intermediates 34 – 37 . Basic hydrolysis of 34 – 37 affords the corresponding carboxylic acid analog series represented by 38 which can then be converted to the desired ester ( 28 ) or amide ( 29 ) series . R = n ‐pentyl…”

“…Efforts to synthesize 4‐, 5‐, 6‐, and 7‐azaindole isomers of adamantyl ester 28 from their corresponding carboxylic acids ( 38 ) have previously been met with difficulty when utilizing the corresponding acyl chloride and similarly under Steglich‐Hassner esterification conditions . However, from an impurity profiling perspective, it is noteworthy that the dehalogenation of 1‐bromoadamantane, when in the presence of silver carbonate, resulted in the inadvertent structural incorporation of the given reaction solvent (dimethylsulfoxide or acetonitrile) in the final reaction step to 28 , affording by‐products 39 and 40 , respectively (Figure ) . Additionally, Košmrlj and co‐workers have recently reported the detection of methyl 2‐acetamido‐3,3‐dimethylbutanoate ( 41 ) in test purchase recreational samples of 5F‐MDMB‐P7AICA ( 25 ) .…”

“…Longworth et al have noted the formation of side products 39 and 40 during attempted syntheses of azaindole SCRA carboxylate esters 28 . similarly, acetamide 41 has been identified as an impurity in illicit samples of 5F‐MDMB‐P7AICA ( 25 )…”

“…A series of 1‐ N ‐ n ‐pentyl azaindole‐3‐carboxamides, 48 – 52 , were prepared by Longworth et al, in order to assess their pharmacological activity at the CB 1 and CB 2 receptors (Table ) . The functional activities of azaindoles 48 , 49 , and 51 could not be determined (EC 50 > 10,000 nM).…”