Bearing in mind the pharmacophoric requirements of both (-)-trans-Delta(9)-tetrahydrocannabinol (THC) and anandamide (AEA), we designed a novel pharmacophore consisting of both a rigid aromatic backbone and a flexible chain with the aim to develop a series of stable and potent ligands of cannabinoid receptors. In this paper we report the synthesis, docking studies, and structure-activity relationships of new resorcinol-anandamide "hybrids" differing in the side chain group. Compounds bearing a 2-methyloctan-2-yl group at position 5 showed a significantly higher affinity for cannabinoid (CB) receptors, in particular when an alkyloxy chain of 7 or 10 carbon atoms was also present at position 1. Derivative 32 was a potent CB(1) and CB(2) ligand, with K(i) values similar to that of WIN 55-212 and potent antinociceptive activity in vivo. Moreover, derivative 38, although less potent, proved to be the most selective ligand for CB(2) receptor (K(i)(CB(1)) = 1 muM, K(i)(CB(2)) = 35 nM).

Brizzi, A., Brizzi, V., Cascio, M.G., Corelli, F., Guida, F., Ligresti, A., et al. (2009). New Resorcinol-Anandamide "Hybrids" as Potent Cannabinoid Receptor Ligands Endowed with antinociceptive activity in vivo. JOURNAL OF MEDICINAL CHEMISTRY, 52(8), 2506-2514 [10.1021/jm8016255].

New Resorcinol-Anandamide "Hybrids" as Potent Cannabinoid Receptor Ligands Endowed with antinociceptive activity in vivo

Brizzi, Antonella;Brizzi, Vittorio;Corelli, Federico;Pasquini, S.;
2009-01-01

Abstract

Bearing in mind the pharmacophoric requirements of both (-)-trans-Delta(9)-tetrahydrocannabinol (THC) and anandamide (AEA), we designed a novel pharmacophore consisting of both a rigid aromatic backbone and a flexible chain with the aim to develop a series of stable and potent ligands of cannabinoid receptors. In this paper we report the synthesis, docking studies, and structure-activity relationships of new resorcinol-anandamide "hybrids" differing in the side chain group. Compounds bearing a 2-methyloctan-2-yl group at position 5 showed a significantly higher affinity for cannabinoid (CB) receptors, in particular when an alkyloxy chain of 7 or 10 carbon atoms was also present at position 1. Derivative 32 was a potent CB(1) and CB(2) ligand, with K(i) values similar to that of WIN 55-212 and potent antinociceptive activity in vivo. Moreover, derivative 38, although less potent, proved to be the most selective ligand for CB(2) receptor (K(i)(CB(1)) = 1 muM, K(i)(CB(2)) = 35 nM).
2009
Brizzi, A., Brizzi, V., Cascio, M.G., Corelli, F., Guida, F., Ligresti, A., et al. (2009). New Resorcinol-Anandamide "Hybrids" as Potent Cannabinoid Receptor Ligands Endowed with antinociceptive activity in vivo. JOURNAL OF MEDICINAL CHEMISTRY, 52(8), 2506-2514 [10.1021/jm8016255].
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Utilizza questo identificativo per citare o creare un link a questo documento: https://hdl.handle.net/11365/25695
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