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

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

Abstract

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.

Keywords

Δ9-Tetrahydrocannabinol AB-CHMINACA AB-FUBINACA AB-PINACA AMB-FUBINACA Cannabinoid CP 55,940 JWH-018 MDMB-CHMICA NPS XLR-11 

Acronyms of the Discussed New Psychoactive Substances (NPS)

Δ9-THC

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

3-CAF

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

4-HTMPIPO

4-Hydroxy-3,3,4-trimethyl-1-(1-pentyl-1H-indol-3-yl)pentan-1-one

5Cl-NNEI

1-(5-Chloropentyl)-N-(naphthalen-1-yl)-1H-indole-3-carboxamide

5Cl-UR-144

[1-(5-Chloropentyl)-1H-indol-3-yl](2,2,3,3-tetramethylcyclopropyl)methanone

5F-AB-FUPPYCA

N-[(2S)-1-Amino-3-methyl-1-oxobutan-2-yl]-1-(5-fluoropentyl)-5-(4-fluorophenyl)-1H-pyrazole-3-carboxamide

5F-AB-PICA

N-[(2S)-1-Amino-3-methyl-1-oxobutan-2-yl]-1-(5-fluoropentyl)-1H-indole-3-carboxamide

5F-AB-PINACA

N-[(2S)-1-Amino-3-methyl-1-oxobutan-2-yl]-1-(5-fluoropentyl)-1H-indazole-3-carboxamide

5F-ADB-PICA

N-[(2S)-1-Amino-3,3-dimethyl-1-oxobutan-2-yl]-1-(5-fluoropentyl)-1H-indole-3-carboxamide

5F-ADB-PINACA

N-[(2S)-1-Amino-3,3-dimethyl-1-oxobutan-2-yl]-1-(5-fluoropentyl)-1H-indazole-3-carboxamide

5F-AKB-57

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

5F-AKB-48-7N

N-(Adamantan-1-yl)-1-(5-fluoropentyl)-1H-pyrrolo[2,3-b]pyridine-3-carboxamide

5F-AMB-PICA

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

5F-AMB-PINACA

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

5F-AMPPPCA

N-(Adamantan-1-yl)-1-(5-fluoropentyl)-4-methyl-5-phenyl-1H-pyrazole-3-carboxamide

5F-APICA

N-(Adamantan-1-yl)-1-(5-fluoropentyl)-1H-indole-3-carboxamide

5F-APINACA

N-(Adamantan-1-yl)-1-(5-fluoropentyl)-1H-indazole-3-carboxamide

5F-CUMYL-PICA

1-(5-Fluoropentyl)-N-(2-phenylpropan-2-yl)-1H-indole-3-carboxamide

5F-CUMYL-PINACA

1-(5-Fluoropentyl)-N-(2-phenylpropan-2-yl)-1H-indazole-3-carboxamide

5F-MDMB-PICA

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

5F-MDMB-PINACA

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

5F-MN-18

1-(5-Fluoropentyl)-N-(naphthalen-1-yl)-1H-indazole-3-carboxamide

5F-NNEI

1-(5-Fluoropentyl)-N-(naphthalen-1-yl)-1H-indole-3-carboxamide

5F-NPB-22-7N

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

5F-PB-22

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

5F-PCN

1-(5-Fluoropentyl)-N-(naphthalen-1-yl)-1H-pyrrolo[3,2-c]pyridine-3-carboxamide

5F-SBD-005

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

A-836339

N-(3-(2-methoxyethyl)-4,5-dimethylthiazol-2(3H)-ylidene)-2,2,3,3-tetramethylcyclopropane-1-carboxamide

AB-001

(Adamantan-1-yl)(1-pentyl-1H-indol-3-yl)methanone

AB-005-azepane

(1-(1-Methylazepan-3-yl)-1H-indol-3-yl)(2,2,3,3-tetramethylcyclopropyl)methanone

AB-CHFUPYCA

N-[(2S)-1-Amino-3-methyl-1-oxobutan-2-yl]-1-(cyclohexylmethyl)-3-(4-fluorophenyl)-1H-pyrazole-5-carboxamide

AB-CHMINACA

N-[(2S)-1-Amino-3-methyl-1-oxobutan-2-yl]-1-(cyclohexylmethyl)-1H-indazole-3-carboxamide

AB-CHMINACA-2H-indazole

N-(1-Amino-3-methyl-1-oxobutan-2-yl)-2-(cyclohexylmethyl)-2H-indazole-3-carboxamide

AB-FUBICA

N-[(2S)-1-Amino-3-methyl-1-oxobutan-2-yl]-1-[(4-fluorophenyl)methyl]-1H-indole-3-carboxamide

AB-FUBINACA

N-[(2S)-1-Amino-3-methyl-1-oxobutan-2-yl]-1-[(4-fluorophenyl)methyl]-1H-indazole-3-carboxamide

AB-PICA

N-[(2S)-1-Amino-3-methyl-1-oxobutan-2-yl]-1-pentyl-1H-indole-3-carboxamide

AB-PINACA

N-[(2S)-1-Amino-3-methyl-1-oxobutan-2-yl]-1-pentyl-1H-indazole-3-carboxamide

ADB-CHMINACA

N-[(2S)-1-Amino-3,3-dimethyl-1-oxobutan-2-yl]-1-(cyclohexylmethyl)-1H-indazole-3-carboxamide

ADB-FUBICA

N-[(2S)-1-Amino-3,3-dimethyl-1-oxobutan-2-yl]-1-[(4-fluorophenyl)methyl]-1H-indole-3-carboxamide

ADB-FUBINACA

N-[(2S)-1-Amino-3,3-dimethyl-1-oxobutan-2-yl]-1-[(4-fluorophenyl)methyl]-1H-indazole-3-carboxamide

ADB-PICA

N-[(2S)-1-Amino-3,3-dimethyl-1-oxobutan-2-yl]-1-pentyl-1H-indole-3-carboxamide

ADSB-FUB-187

7-Chloro-N-[(2S)-1-({2-[(cyclopropanesulfonyl)amino]ethyl}amino)-3,3-dimethyl-1-oxobutan-2-yl]-1-[(4-fluorophenyl)methyl]-1H-indazole-3-carboxamide

APP-FUBINACA

N-[(2S)-1-Amino-1-oxo-3-phenylpropan-2-yl]-1-[(4-fluorophenyl)methyl]-1H-indazole-3-carboxamide

AKB-48

N-(Adamantan-1-yl)-1-pentyl-1H-indazole-3-carboxamide

AM-2201

[1-(5-Fluoropentyl)-1H-indol-3-yl](naphthalen-1-yl)methanone

AMB-CHMICA

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

AMB-CHMINACA

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

AMB-FUBICA

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

AMB-FUBINACA

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

AMB-PICA

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

AMB-PINACA

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

AMPPPCA

N-(Adamantan-1-yl)-4-methyl-1-pentyl-5-phenyl-1H-pyrazole-3-carboxamide

APICA

N-(Adamantan-1-yl)-1-pentyl-1H-indole-3-carboxamide

APINAC

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

APINACA

N-(Adamantan-1-yl)-1-pentyl-1H-indazole-3-carboxamide

APINACA-2H-indazole

N-(Adamantan-1-yl)-2-pentyl-2H-indazole-3-carboxamide

BB-22

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

BIM-018

(Naphthalen-1-yl)(1-pentyl-1H-benzimidazol-2-yl)methanone

BiPICANA

N-(Naphthalen-1-yl)-1-pentyl-N-(1-pentyl-1H-indole-3-carbonyl)-1H-indole-3-carboxamide

BzODZ-EPyr

3-Benzyl-5-(1-(2-(pyrrolidin-1-yl)ethyl)-1H-indol-3-yl)-1,2,4-oxadiazole

CBL-018

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

CBL-2201

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

CP 47,497-C8

2-[(1S,3R)-3-Hydroxycyclohexyl]-5-(2-methylnonan-2-yl)phenol

CUMYL-4CN-B7AICA

1-(4-Cyanobutyl)-N-(2-phenylpropan-2-yl)-1H-pyrrolo[2,3-b]pyridine-3-carboxamide

CUMYL-5F-P7AICA

1-(5-Fluoropentyl)-N-(2-phenylpropan-2-yl)-1H-pyrrolo[2,3-b]pyridine-3-carboxamide

CUMYL-BICA

1-Butyl-N-(2-phenylpropan-2-yl)-1H-indole-3-carboxamide

CUMYL-BINACA

1-Butyl-N-(2-phenylpropan-2-yl)-1H-indazole-3-carboxamide

CUMYL-CHMICA

1-(Cyclohexylmethyl)-N-(2-phenylpropan-2-yl)-1H-indole-3-carboxamide

CUMYL-CHMINACA

1-(Cyclohexylmethyl)-N-(2-phenylpropan-2-yl)-1H-indazole-3-carboxamide

CUMYL-FUBICA

1-(4-Fluorobenzyl)-N-(2-phenylpropan-2-yl)-1H-indole-3-carboxamide

CUMYL-FUBINACA

1-(4-Fluorobenzyl)-N-(2-phenylpropan-2-yl)-1H-indazole-3-carboxamide

CUMYL-PEGACLONE

5-Pentyl-2-(2-phenylpropan-2-yl)-2,5-dihydro-1H-pyrido[4,3-b]indol-1-one

CUMYL-PICA

1-Pentyl-N-(2-phenylpropan-2-yl)-1H-indole-3-carboxamide

CUMYL-PINACA

1-Pentyl-N-(2-phenylpropan-2-yl)-1H-indazole-3-carboxamide

DP-UR-144

(1H-Indol-3-yl)(2,2,3,3-tetramethylcyclopropyl)methanone

EG-018

(Naphthalen-1-yl)(9-pentyl-9H-carbazol-3-yl)methanone

EG-2201

[9-(5-Fluoropentyl)-9H-carbazol-3-yl](naphthalen-1-yl)methanone

FAB-144

[1-(5-Fluoropentyl)-1H-indazol-3-yl](2,2,3,3-tetramethylcyclopropyl)methanone

FDU-NNEI

1-[(4-Fluorophenyl)methyl]-N-(naphthalen-1-yl)-1H-indole-3-carboxamide

FDU-PB-22

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

FUB-144

{1-[(4-Fluorophenyl)methyl]-1H-indol-3-yl}(2,2,3,3-tetramethylcyclopropyl)methanone

FUB-AKB-48

N-(Adamantan-1-yl)-1-(4-fluorobenzyl)-1H-indazole-3-carboxamide

FUB-PB-22

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

FUBIMINA

[1-(5-Fluoropentyl)-1H-benzimidazol-2-yl](naphthalen-1-yl)methanone

JWH-018

(Naphthalen-1-yl)(1-pentyl-1H-indol-3-yl)methanone

M-5FPIC

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

MCBH-1

1-(Cyclohexylmethyl)-2-(4-ethoxybenzyl)-N,N-diethyl-1H-benzo[d]imidazole-5-carboxamide

M-CHMIC

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

MDMB-CHMCZCA

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

MDMB-CHMICA

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

MDMB-CHMINACA

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

MDMB-FUBICA

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

MDMB-FUBINACA

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

MDMB-PICA

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

MDMB-PINACA

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

MEPIRAPIM

(4-Methylpiperazin-1-yl)(1-pentyl-1H-indol-3-yl)methanone

MN-001

(1-Pentyl-1H-indol-3-yl)(2,2,3,3-tetramethylcyclopropyl)methanone

MN-18

N-(Naphthalen-1-yl)-1-pentyl-1H-indazole-3-carboxamide

MN-25

7-Methoxy-1-[2-(morpholin-4-yl)ethyl]-N-[(1S,2S,4R)-1,3,3-trimethylbicyclo[2.2.1]heptan-2-yl]-1H-indole-3-carboxamide

NMP-7

(9-Pentyl-9H-carbazol-3-yl)(piperidin-1-yl)methanone

NNEI

N-(Naphthalen-1-yl)-1-pentyl-1H-indazole-3-carboxamide

NNEI-2H-indazole

N-(Naphthalen-1-yl)-2-pentyl-2H-indazole-3-carboxamide

NNL-3

1-{[1-(5-Fluoropentyl)-1H-pyrrolo[2,3-b]pyridine-3-carbonyl]oxy}-1H-benzotriazole

N-Phenyl-SDB-006

1-Pentyl-N-phenyl-1H-indole-3-carboxamide

Org-28611

(S)-(1-(Cyclohexylmethyl)-7-methoxy-1H-indol-3-yl)(3,4-dimethylpiperazin-1-yl)methanone

PB-22

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

PTI-1

N-Ethyl-N-{[2-(1-pentyl-1H-indol-3-yl)-1,3-thiazol-4-yl]methyl}ethanamine

PTI-2

N-(2-Methoxyethyl)-N-{[2-(1-pentyl-1H-indol-3-yl)-1,3-thiazol-4-yl]methyl}propan-2-amine

QMPSB

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

RCS-4-N-Me

(4-Methoxyphenyl)(1-methyl-1H-indol-3-yl)methanone

SBD-005

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

SBD-006

N-Benzyl-1-pentyl-1H-indole-3-carboxamide

THJ-018

(Naphthalen-1-yl)(1-pentyl-1H-indazol-3-yl)methanone

THJ-2201

[1-(5-Fluoropentyl)-1H-indazol-3-yl](naphthalen-1-yl)methanone

TMCP-020

(1-Heptyl-1H-indol-3-yl)(2,2,3,3-tetramethylcyclopropyl)methanone

UR-144

(1-Pentyl-1H-indol-3-yl)(2,2,3,3-tetramethylcyclopropyl)methanone

XLR-11

[1-(5-Fluoropentyl)-1H-indol-3-yl](2,2,3,3-tetramethylcyclopropyl)methanone

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Copyright information

© 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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