title: Structure-affinity relationships and pharmacological characterization of new alkyl-resorcinol cannabinoid receptor ligands: Identification of a dual cannabinoid receptor/TRPA1 channel agonist.
abstract: In our ongoing program aimed at deeply investigating the endocannabinoid system (ES), a set of new alkyl-resorcinol derivatives was prepared focusing on the nature and the importance of the carboxamide functionality. Binding studies on CB1 and CB2 receptors, monoacylglycerol lipase (MAGL) and fatty acid amide hydrolase (FAAH) showed that some of the newly developed compounds behaved as very potent cannabinoid receptor ligands (Ki in the nanomolar range) while, however, none of them was able to inhibit MAGL and/or FAAH. Derivative 11 was a potent CB1 and CB2 ligand, with Ki values similar to WIN 55,212, exhibiting a CB1 and CB2 agonist profile in vitro. In the formalin test of peripheral acute and inflammatory pain in mice, this compound showed a weak and delayed antinociceptive effect against the second phase of the nocifensive response, exhibiting, interestingly, a quite potent transient receptor potential ankyrin type-1 (TRPA1) channel agonist activity. Moreover, derivative 14, characterized by lower affinity but higher CB2 selectivity than 11, proved to behave as a weak CB2 competitive inverse agonist.
authors: Dipartimento di Biotecnologie, Chimica e Farmacia, Università degli Studi di Siena, Via A. Moro 2, 53100 Siena, Italy. Electronic address: antonella.brizzi@unisi.it.
authors: Antonella
authors: A
authors: Brizzi
authors: Dipartimento di Farmacia e Scienze della Salute e della Nutrizione, Università della Calabria, 87036 Arcavacata di Rende, Cosenza, Italy.
authors: Francesca
authors: F
authors: Aiello
authors: Institute of Medical Sciences, University of Aberdeen, Foresterhill, Aberdeen, Scotland, UK.
authors: Pietro
authors: P
authors: Marini
authors: Institute of Medical Sciences, University of Aberdeen, Foresterhill, Aberdeen, Scotland, UK; Endocannabinoid Research Group, Istituto di Chimica Biomolecolare, Consiglio Nazionale delle Ricerche, Via Campi Flegrei 34, 80078 Pozzuoli, Napoli, Italy.
authors: Maria Grazia
authors: MG
authors: Cascio
authors: Dipartimento di Biotecnologie, Chimica e Farmacia, Università degli Studi di Siena, Via A. Moro 2, 53100 Siena, Italy. Electronic address: federico.corelli@unisi.it.
authors: Federico
authors: F
authors: Corelli
authors: Dipartimento di Biotecnologie, Chimica e Farmacia, Università degli Studi di Siena, Via A. Moro 2, 53100 Siena, Italy.
authors: Vittorio
authors: V
authors: Brizzi
authors: Endocannabinoid Research Group, Istituto di Cibernetica, Consiglio Nazionale delle Ricerche, Via Campi Flegrei 34, 80078 Pozzuoli, Napoli, Italy.
authors: Luciano
authors: L
authors: De Petrocellis
authors: Endocannabinoid Research Group, Istituto di Chimica Biomolecolare, Consiglio Nazionale delle Ricerche, Via Campi Flegrei 34, 80078 Pozzuoli, Napoli, Italy.
authors: Alessia
authors: A
authors: Ligresti
authors: Dipartimento di Medicina Sperimentale, Sezione di Farmacologia 'L. Donatelli', Seconda Università di Napoli, Via Costantinopoli 16, 80138 Napoli, Italy.
authors: Livio
authors: L
authors: Luongo
authors: Dipartimento di Biotecnologie, Chimica e Farmacia, Università degli Studi di Siena, Via A. Moro 2, 53100 Siena, Italy.
authors: Stefania
authors: S
authors: Lamponi
authors: Dipartimento di Medicina Sperimentale, Sezione di Farmacologia 'L. Donatelli', Seconda Università di Napoli, Via Costantinopoli 16, 80138 Napoli, Italy.
authors: Sabatino
authors: S
authors: Maione
authors: Institute of Medical Sciences, University of Aberdeen, Foresterhill, Aberdeen, Scotland, UK.
authors: Roger G
authors: RG
authors: Pertwee
authors: Endocannabinoid Research Group, Istituto di Chimica Biomolecolare, Consiglio Nazionale delle Ricerche, Via Campi Flegrei 34, 80078 Pozzuoli, Napoli, Italy.
authors: Vincenzo
authors: V
authors: Di Marzo
mesh_terms: D000700:Analgesics / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology*; D000818:Animals; D016466:CHO Cells; D015220:Calcium Channels; D002470:Cell Survival / Q000187:drug effects; D002478:Cells, Cultured; D003412:Cricetulus; D004305:Dose-Response Relationship, Drug; D006801:Humans; D008024:Ligands; D008297:Male; D051379:Mice; D015394:Molecular Structure; D041681:NIH 3T3 Cells; D009419:Nerve Tissue Proteins / Q000819:agonists*; D059225:Nociception / Q000187:drug effects; D010146:Pain / Q000188:drug therapy; D010147:Pain Measurement / Q000187:drug effects; D043884:Receptor, Cannabinoid, CB1 / Q000819:agonists*; D043885:Receptor, Cannabinoid, CB2 / Q000819:agonists*; D012118:Resorcinols / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology*; D013329:Structure-Activity Relationship; D000074025:TRPA1 Cation Channel; D050051:Transient Receptor Potential Channels / Q000819:agonists*
chemical_list: D000700:Analgesics; C588309:CNR2 protein, human; D015220:Calcium Channels; D008024:Ligands; D009419:Nerve Tissue Proteins; D043884:Receptor, Cannabinoid, CB1; D043885:Receptor, Cannabinoid, CB2; D012118:Resorcinols; D000074025:TRPA1 Cation Channel; C473350:TRPA1 protein, human; D050051:Transient Receptor Potential Channels; C031389:resorcinol
keywords: Alkyl-resorcinol derivatives; Anandamide; Cannabinoid ligands; Endocannabinoids; Lipid modulators; Structure–affinity relationships; Transient receptor potential ankyrin type-1 channel