New Resorcinol-Anandamide "Hybrids" as Potent Cannabinoid Receptor Ligands Endowed with Antinociceptive Activity in Vivo

被引：16

作者：

Brizzi, Antonella ^{[1
]}

Brizzi, Vittorio ^{[1
]}

Cascio, Maria Grazia ^{[2
]}

Corelli, Federico ^{[1
]}

Guida, Francesca

Ligresti, Alessia ^{[2
]}

Maione, Sabatino

Martinelli, Adriano ^{[3
]}

Pasquini, Serena ^{[1
]}

Tuccinardi, Tiziano ^{[3
,4
]}

Di Marzo, Vincenzo ^{[2
]}

机构：

[1] Univ Siena, Dipartimento Farm Chim Tecnol, I-53100 Siena, Italy

[2] CNR, Ist Chim Biomol, Endocannabinoid Res Grp, I-80078 Naples, Italy

[3] Univ Pisa, Dipartimento Sci Farmaceut, I-56126 Pisa, Italy

[4] Temple Univ, Coll Sci & Technol, Ctr Biotechnol, Sbarro Inst Canc Res & Mol Med, Philadelphia, PA 19122 USA

来源：

JOURNAL OF MEDICINAL CHEMISTRY | 2009年 / 52卷 / 08期

关键词：

CARDIOMETABOLIC RISK-FACTORS; ENDOCANNABINOID SYSTEM; FORMALIN TEST; MOLECULAR CHARACTERIZATION; SCORING PROPERTIES; SMOKING-CESSATION; LYSINE RESIDUE; BRAIN; ANALOGS; BINDING;

D O I：

10.1021/jm8016255

中图分类号：

R914 [药物化学];

学科分类号：

100701 ;

摘要：

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, receptor (K(i)(CB(1)) = 1 mu M, K(i)(CB(2)) = 35 nM).

引用

页码：2506 / 2514

页数：9

共 60 条

[11] Design, synthesis, binding, and molecular modeling studies of new potent ligands of cannabinoid receptors [J].