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Structure-affinity relationships and pharmacological characterization of new alkyl-resorcinol cannabinoid receptor ligands: Identification of a dual cannabinoid receptor/TRPA1 channel agonist.
Bioorg Med Chem. 2014 Sep 01; 22(17):4770-83.BM

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+Show Affiliations

Dipartimento di Biotecnologie, Chimica e Farmacia, Università degli Studi di Siena, Via A. Moro 2, 53100 Siena, Italy. Electronic address: antonella.brizzi@unisi.it.Dipartimento di Farmacia e Scienze della Salute e della Nutrizione, Università della Calabria, 87036 Arcavacata di Rende, Cosenza, Italy.Institute of Medical Sciences, University of Aberdeen, Foresterhill, Aberdeen, Scotland, UK.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.Dipartimento di Biotecnologie, Chimica e Farmacia, Università degli Studi di Siena, Via A. Moro 2, 53100 Siena, Italy. Electronic address: federico.corelli@unisi.it.Dipartimento di Biotecnologie, Chimica e Farmacia, Università degli Studi di Siena, Via A. Moro 2, 53100 Siena, Italy.Endocannabinoid Research Group, Istituto di Cibernetica, Consiglio Nazionale delle Ricerche, Via Campi Flegrei 34, 80078 Pozzuoli, Napoli, Italy.Endocannabinoid Research Group, Istituto di Chimica Biomolecolare, Consiglio Nazionale delle Ricerche, Via Campi Flegrei 34, 80078 Pozzuoli, Napoli, Italy.Dipartimento di Medicina Sperimentale, Sezione di Farmacologia 'L. Donatelli', Seconda Università di Napoli, Via Costantinopoli 16, 80138 Napoli, Italy.Dipartimento di Biotecnologie, Chimica e Farmacia, Università degli Studi di Siena, Via A. Moro 2, 53100 Siena, Italy.Dipartimento di Medicina Sperimentale, Sezione di Farmacologia 'L. Donatelli', Seconda Università di Napoli, Via Costantinopoli 16, 80138 Napoli, Italy.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.

Pub Type(s)

Journal Article

Language

eng

PubMed ID

25065940

Citation

Brizzi, Antonella, et al. "Structure-affinity Relationships and Pharmacological Characterization of New Alkyl-resorcinol Cannabinoid Receptor Ligands: Identification of a Dual Cannabinoid receptor/TRPA1 Channel Agonist." Bioorganic & Medicinal Chemistry, vol. 22, no. 17, 2014, pp. 4770-83.
Brizzi A, Aiello F, Marini P, et al. Structure-affinity relationships and pharmacological characterization of new alkyl-resorcinol cannabinoid receptor ligands: Identification of a dual cannabinoid receptor/TRPA1 channel agonist. Bioorg Med Chem. 2014;22(17):4770-83.
Brizzi, A., Aiello, F., Marini, P., Cascio, M. G., Corelli, F., Brizzi, V., De Petrocellis, L., Ligresti, A., Luongo, L., Lamponi, S., Maione, S., Pertwee, R. G., & Di Marzo, V. (2014). Structure-affinity relationships and pharmacological characterization of new alkyl-resorcinol cannabinoid receptor ligands: Identification of a dual cannabinoid receptor/TRPA1 channel agonist. Bioorganic & Medicinal Chemistry, 22(17), 4770-83. https://doi.org/10.1016/j.bmc.2014.07.006
Brizzi A, et al. Structure-affinity Relationships and Pharmacological Characterization of New Alkyl-resorcinol Cannabinoid Receptor Ligands: Identification of a Dual Cannabinoid receptor/TRPA1 Channel Agonist. Bioorg Med Chem. 2014 Sep 1;22(17):4770-83. PubMed PMID: 25065940.
* Article titles in AMA citation format should be in sentence-case
TY - JOUR T1 - Structure-affinity relationships and pharmacological characterization of new alkyl-resorcinol cannabinoid receptor ligands: Identification of a dual cannabinoid receptor/TRPA1 channel agonist. AU - Brizzi,Antonella, AU - Aiello,Francesca, AU - Marini,Pietro, AU - Cascio,Maria Grazia, AU - Corelli,Federico, AU - Brizzi,Vittorio, AU - De Petrocellis,Luciano, AU - Ligresti,Alessia, AU - Luongo,Livio, AU - Lamponi,Stefania, AU - Maione,Sabatino, AU - Pertwee,Roger G, AU - Di Marzo,Vincenzo, Y1 - 2014/07/12/ PY - 2014/03/07/received PY - 2014/06/24/revised PY - 2014/07/02/accepted PY - 2014/7/29/entrez PY - 2014/7/30/pubmed PY - 2015/4/7/medline KW - Alkyl-resorcinol derivatives KW - Anandamide KW - Cannabinoid ligands KW - Endocannabinoids KW - Lipid modulators KW - Structure–affinity relationships KW - Transient receptor potential ankyrin type-1 channel SP - 4770 EP - 83 JF - Bioorganic & medicinal chemistry JO - Bioorg Med Chem VL - 22 IS - 17 N2 - 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. SN - 1464-3391 UR - https://www.unboundmedicine.com/medline/citation/25065940/Structure_affinity_relationships_and_pharmacological_characterization_of_new_alkyl_resorcinol_cannabinoid_receptor_ligands:_Identification_of_a_dual_cannabinoid_receptor/TRPA1_channel_agonist_ L2 - https://linkinghub.elsevier.com/retrieve/pii/S0968-0896(14)00509-4 DB - PRIME DP - Unbound Medicine ER -