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Comprehensive Characterization of a Systematic Library of Alkyl and Alicyclic Synthetic Cannabinoids Related to CUMYL-PICA, CUMYL-BUTICA, CUMYL-CBMICA, and CUMYL-PINACA.
Janssens, Liesl K; Ametovski, Adam; Sparkes, Eric; Boyd, Rochelle; Lai, Felcia; Maloney, Callan J; Rhook, Dane; Gerona, Roy R; Connolly, Matthew; Liu, Huiling; Hibbs, David E; Cairns, Elizabeth A; Banister, Samuel D; Stove, Christophe P.
Afiliação
  • Janssens LK; Laboratory of Toxicology, Department of Bioanalysis, Faculty of Pharmaceutical Sciences, Ghent University, 9000 Ghent, Belgium.
  • Ametovski A; The Lambert Initiative for Cannabinoid Therapeutics, Brain and Mind Centre, The University of Sydney, Sydney, NSW 2050, Australia.
  • Sparkes E; School of Chemistry, The University of Sydney, Sydney, NSW 2006, Australia.
  • Boyd R; The Lambert Initiative for Cannabinoid Therapeutics, Brain and Mind Centre, The University of Sydney, Sydney, NSW 2050, Australia.
  • Lai F; School of Chemistry, The University of Sydney, Sydney, NSW 2006, Australia.
  • Maloney CJ; The Lambert Initiative for Cannabinoid Therapeutics, Brain and Mind Centre, The University of Sydney, Sydney, NSW 2050, Australia.
  • Rhook D; School of Psychology, The University of Sydney, Sydney, NSW 2006, Australia.
  • Gerona RR; School of Pharmacy, The University of Sydney, Sydney, NSW 2006, Australia.
  • Connolly M; The Lambert Initiative for Cannabinoid Therapeutics, Brain and Mind Centre, The University of Sydney, Sydney, NSW 2050, Australia.
  • Liu H; School of Chemistry, The University of Sydney, Sydney, NSW 2006, Australia.
  • Hibbs DE; The Lambert Initiative for Cannabinoid Therapeutics, Brain and Mind Centre, The University of Sydney, Sydney, NSW 2050, Australia.
  • Cairns EA; School of Chemistry, The University of Sydney, Sydney, NSW 2006, Australia.
  • Banister SD; Clinical Toxicology and Environmental Biomonitoring Laboratory, University of California, San Francisco, California 94143, United States.
  • Stove CP; Chiron AS, 7041 Trondheim, Norway.
ACS Chem Neurosci ; 14(1): 35-52, 2023 01 04.
Article em En | MEDLINE | ID: mdl-36530139
ABSTRACT
Over 200 synthetic cannabinoid receptor agonists (SCRAs) have been identified as new psychoactive substances. Effective monitoring and characterization of SCRAs are hindered by the rapid pace of structural evolution. Ahead of possible appearance on the illicit drug market, new SCRAs were synthesized to complete a systematic library of cumyl-indole- (e.g., CUMYL-CPrMICA, CUMYL-CPMICA) and cumyl-indazole-carboxamides (e.g., CUMYL-CPrMINACA, CUMYL-CPMINACA), encompassing butyl, pentyl, cyclopropylmethyl, cyclobutylmethyl, cyclopentylmethyl, and cyclohexylmethyl tails. Comprehensive pharmacological characterization was performed with three assay formats, monitoring the recruitment of either wild-type or C-terminally truncated (ßarr2d366) ß-arrestin2 to the activated cannabinoid 1 receptor (CB1) or monitoring Gßγ-mediated membrane hyperpolarization. Altered compound characterization was observed when comparing derived potency (EC50) and efficacy (Emax) values from both assays monitoring the same or a different signaling event, whereas ranges and ranking orders were similar. Structure-activity relationships (SAR) were assessed in threefold, resulting in the identification of the pendant tail as a critical pharmacophore, with the optimal chain length for CB1 activation approximating an n-pentyl (e.g., cyclopentylmethyl or cyclohexylmethyl tail). The activity of the SCRAs encompassing cyclic tails decreased with decreasing number of carbons forming the cyclic moiety, with CUMYL-CPrMICA showing the least CB1 activity in all assay formats. The SARs were rationalized via molecular docking, demonstrating the importance of the optimal steric contribution of the hydrophobic tail. While SAR conclusions remained largely unchanged, the differential compound characterization by both similar and different assay designs emphasizes the importance of detailing specific assay characteristics to allow adequate interpretation of potencies and efficacies.
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Texto completo: 1 Coleções: 01-internacional Base de dados: MEDLINE Assunto principal: Canabinoides Tipo de estudo: Prognostic_studies Idioma: En Revista: ACS Chem Neurosci Ano de publicação: 2023 Tipo de documento: Article País de afiliação: Bélgica
Texto completo
Adicionar na Minha BVS
Imprimir
XML
PubMed Links
Buscar no Google

Texto completo: 1 Coleções: 01-internacional Base de dados: MEDLINE Assunto principal: Canabinoides Tipo de estudo: Prognostic_studies Idioma: En Revista: ACS Chem Neurosci Ano de publicação: 2023 Tipo de documento: Article País de afiliação: Bélgica