The Chemistry and Pharmacology of Synthetic Cannabinoid Receptor Agonist New Psychoactive Substances: Evolution

  • Samuel D. BanisterEmail author
  • Mark Connor
Part of the Handbook of Experimental Pharmacology book series (HEP, volume 252)


Synthetic cannabinoid receptor agonists (SCRAs) are the largest and most structurally diverse class of new psychoactive substances (NPS). Although the earliest SCRA NPS were simply repurposed from historical academic manuscripts or pharmaceutical patents describing cannabinoid ligands, recent examples bear hallmarks of rational design. SCRA NPS manufacturers have applied traditional medicinal chemistry strategies (such as molecular hybridization, bioisosteric replacement, and scaffold hopping) to existing cannabinoid templates in order to generate new molecules that circumvent structure-based legislation. Most SCRAs potently activate cannabinoid type 1 and type 2 receptors (CB1 and CB2, respectively), with the former contributing to the psychoactivity of these substances. SCRAs are generally more toxic than the Δ9-tetrahydrocannabinol (Δ9-THC) found in cannabis, and this may be due to ligand bias, metabolism, or off-target activity. This chapter will chart the evolution of recently identified SCRA NPS chemotypes, as well as their putative manufacturing by-products and thermolytic degradants, and describe structure-activity relationships within each class.



Acronyms of the Discussed New Psychoactive Substances (NPS)


(6aR,10aR)-6,6,9-Trimethyl-3-pentyl-6a,7,8,10a-tetrahydro-6H-dibenzo[b,d]pyran-1-ol (Δ9-tetrahydrocannabinol)


Naphthalen-2-yl 1-(2-fluorophenyl)-1H-indazole-3-carboxylate


















Adamantan-1-yl 1-(5-fluoropentyl)-1H-indazole-3-carboxylate




Methyl (2S)-2-{[1-(5-fluoropentyl)-1H-indole-3-carbonyl]amino}-3-methylbutanoate


Methyl (2S)-2-{[1-(5-fluoropentyl)-1H-indazole-3-carbonyl]amino}-3-methylbutanoate












Methyl (2S)-2-{[1-(5-fluoropentyl)-1H-indole-3-carbonyl]amino}-3,3-dimethylbutanoate


Methyl (2S)-2-{[1-(5-fluoropentyl)-1H-indazole-3-carbonyl]amino}-3,3-dimethylbutanoate






Quinolin-8-yl 1-(5-fluoropentyl)-1H-pyrrolo[2,3-b]pyridine-3-carboxylate


Quinolin-8-yl 1-(5-fluoropentyl)-1H-indole-3-carboxylate




Naphthalen-1-yl 1-(5-fluoropentyl)-1H-indazole-3-carboxylate






































Methyl (2S)-2-{[1-(cyclohexylmethyl)-1H-indole-3-carbonyl]amino}-3-methylbutanoate


Methyl (2S)-2-{[1-(cyclohexylmethyl)-1H-indazole-3-carbonyl]amino}-3-methylbutanoate


Methyl (2S)-2-({1-[(4-fluorophenyl)methyl]-1H-indole-3-carbonyl}amino)-3-methylbutanoate


Methyl (2S)-2-({1-[(4-fluorophenyl)methyl]-1H-indazole-3-carbonyl}amino)-3-methylbutanoate


Methyl (2S)-2-[(1-pentyl-1H-indole-3-carbonyl)amino]-3-methylbutanoate


Methyl (2S)-2-[(1-pentyl-1H-indazole-3-carbonyl)amino]-3-methylbutanoate






Adamantan-1-yl 1-pentyl-1H-indazole-3-carboxylate






Quinolin-8-yl 1-(cyclohexylmethyl)-1H-indole-3-carboxylate








Naphthalen-1-yl 1-pentyl-1H-indole-3-carboxylate


Naphthalen-1-yl 1-(5-fluoropentyl)-1H-indole-3-carboxylate

CP 47,497-C8



































Naphthalen-1-yl 1-[(4-fluorophenyl)methyl]-1H-indole-3-carboxylate






Quinolin-8-yl 1-[(4-fluorophenyl)methyl]-1H-indole-3-carboxylate






Methyl 1-(5-fluoropentyl)-1H-indole-3-carboxylate




Methyl 1-(cyclohexylmethyl)-1H-indole-3-carboxylate


Methyl (2S)-2-{[9-(cyclohexylmethyl)-9H-carbazole-3-carbonyl]amino}-3,3-dimethylbutanoate


Methyl (2S)-2-{[1-(cyclohexylmethyl)-1H-indole-3-carbonyl]amino}-3,3-dimethylbutanoate


Methyl (2S)-2-{[1-(cyclohexylmethyl)-1H-indazole-3-carbonyl]amino}-3,3-dimethylbutanoate


Methyl (2S)-2-({1-[(4-fluorophenyl)methyl]-1H-indole-3-carbonyl}amino)-3,3-dimethylbutanoate


Methyl (2S)-2-({1-[(4-fluorophenyl)methyl]-1H-indazole-3-carbonyl}amino)-3,3-dimethylbutanoate


Methyl (2S)-3,3-dimethyl-2-[(1-pentyl-1H-indole-3-carbonyl)amino]butanoate


Methyl (2S)-3,3-dimethyl-2-[(1-pentyl-1H-indazole-3-carbonyl)amino]butanoate






















Quinolin-8-yl 1-pentyl-1H-indole-3-carboxylate






Quinolin-8-yl 4-methyl-3-(piperidine-1-sulfonyl)benzoate




Naphthalen-1-yl 1-pentyl-1H-indazole-3-carboxylate














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© Springer International Publishing AG, part of Springer Nature 2018

Authors and Affiliations

  1. 1.Department of PathologyStanford UniversityStanfordUSA
  2. 2.Brain and Mind CentreThe University of SydneySydneyAustralia
  3. 3.Faculty of Medicine and Health SciencesMacquarie UniversitySydneyAustralia

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