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Bioorg Med Chem. 2014 Sep 1;22(17):4770-83. doi: 10.1016/j.bmc.2014.07.006. Epub 2014 Jul 12.

Structure-affinity relationships and pharmacological characterization of new alkyl-resorcinol cannabinoid receptor ligands: Identification of a dual cannabinoid receptor/TRPA1 channel agonist.

Author information

1
Dipartimento di Biotecnologie, Chimica e Farmacia, Università degli Studi di Siena, Via A. Moro 2, 53100 Siena, Italy. Electronic address: antonella.brizzi@unisi.it.
2
Dipartimento di Farmacia e Scienze della Salute e della Nutrizione, Università della Calabria, 87036 Arcavacata di Rende, Cosenza, Italy.
3
Institute of Medical Sciences, University of Aberdeen, Foresterhill, Aberdeen, Scotland, UK.
4
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.
5
Dipartimento di Biotecnologie, Chimica e Farmacia, Università degli Studi di Siena, Via A. Moro 2, 53100 Siena, Italy. Electronic address: federico.corelli@unisi.it.
6
Dipartimento di Biotecnologie, Chimica e Farmacia, Università degli Studi di Siena, Via A. Moro 2, 53100 Siena, Italy.
7
Endocannabinoid Research Group, Istituto di Cibernetica, Consiglio Nazionale delle Ricerche, Via Campi Flegrei 34, 80078 Pozzuoli, Napoli, Italy.
8
Endocannabinoid Research Group, Istituto di Chimica Biomolecolare, Consiglio Nazionale delle Ricerche, Via Campi Flegrei 34, 80078 Pozzuoli, Napoli, Italy.
9
Dipartimento di Medicina Sperimentale, Sezione di Farmacologia 'L. Donatelli', Seconda Università di Napoli, Via Costantinopoli 16, 80138 Napoli, Italy.

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.

KEYWORDS:

Alkyl-resorcinol derivatives; Anandamide; Cannabinoid ligands; Endocannabinoids; Lipid modulators; Structure–affinity relationships; Transient receptor potential ankyrin type-1 channel

PMID:
25065940
DOI:
10.1016/j.bmc.2014.07.006
[Indexed for MEDLINE]

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