A Synthetic Route to Anandamide Analogues Carrying a Substituent at the Terminal Carbon and an Acetylene Group in the End Pentyl Chain

Organix, Inc., 240 Salem Street, Woburn, MA 01801, USA
Tetrahedron Letters (Impact Factor: 2.38). 11/2004; 45(28):5449-5451. DOI: 10.1016/j.tetlet.2004.05.071


A versatile sequence is developed for the synthesis of anandamide analogues with an acetylene group in the end pentyl chain carrying a substituent at the terminal carbon of the chain. These analogues are important for SAR studies of the endocannabinoid, anandamide.

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    ABSTRACT: Recent advances in the synthesis of endocannabinoid-related ligands for the period 2001-2004 are covered in this review. During this period the first solid phase synthesis of anandamide (AEA) analogs was developed, which allows modification at both the head group and the end pentyl chain. Synthesis of water-soluble prodrugs of noladin ether was reported, which are chemically stable, rapidly release noladin ether under enzymatic conditions and are shown to reduce intraocular pressure. The structure-activity relationships (SAR) of alkylcarbamic acid aryl esters and the discovery of potent archidonylsulfonyl derivatives as fatty acid amide hydrolase (FAAH) inhibitors are summarized. Recent synthetic developments in the controversial area of anandamide membrane transporter (AMT) inhibitors are also discussed.
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    ABSTRACT: The structure-activity relationship (SAR) of the end pentyl chain in anandamide (AEA) has been established to be very similar to that of Delta(9)-tetrahydrocannabinol (Delta(9)-THC). In order to broaden our understanding of the structural similarities between AEA and THC, hybrid structures 1-3 were designed. In these hybrids the aromatic ring of THC-DMH was linked to the AEA moiety through an ether linkage with the oxygen of the phenol of THC. Hybrid 1 (O-2220) was found to have very high binding affinity to CB1 receptors (K(i)=8.5 nM), and it is interesting to note that the orientation of the side chain with respect to the oxygen in the phenol is the same as in THCs. To further explore the SAR in this series the terminal carbon of the side chain was modified by adding different substituents. Several such analogs were synthesized and tested for their CB1 and CB2 binding affinities and in vivo activity (tetrad tests). The details of the synthesis and the biological activity of these compounds are described.
    Bioorganic & medicinal chemistry 01/2008; 15(24):7850-64. DOI:10.1016/j.bmc.2007.08.039 · 2.79 Impact Factor
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