title: Design, synthesis, and binding studies of new potent ligands of cannabinoid receptors.
abstract: Despite their different chemical structures, delta9-tetrahydrocannabinol (THC) and anandamide (AEA) have common pharmacological properties. This study was aimed at finding new cannabinoid receptor ligands that overcome the instability of AEA and its analogues. To this end we planned the synthesis of a series of compounds which retained both a rigid structure, like that of plant cannabinoids, and a flexible portion similar to that of anandamide. Binding studies on CB1 and CB2 receptors, anandamide membrane transporter (AMT), and fatty acid amide hydrolase (FAAH) showed that some of the newly developed compounds have high affinity and specificity for cannabinoid CB1 and CB2 receptors. Compound 25 is a potent CB1 and CB2 ligand, with affinity constants significantly lower than AEA and similar to WIN 55-212, compound 52 is a potent CB2 ligand, although not very selective over CB1 receptors, and compound 43 is CB2 ligand, with at least a 26-fold selectivity over CB1 receptors. Compound 25 behaved as a inverse agonist at CB1 receptors as assessed in the cyclic AMP functional assay.
authors.affiliation: Dipartimento Farmaco Chimico Tecnologico, Università degli Studi di Siena, Via A. Moro 2, 53100 Siena, Italy. brizzi3@unisi.it
authors.forename: Antonella
authors.initials: A
authors.lastname: Brizzi
authors.forename: Vittorio
authors.initials: V
authors.lastname: Brizzi
authors.forename: Maria Grazia
authors.initials: MG
authors.lastname: Cascio
authors.forename: Tiziana
authors.initials: T
authors.lastname: Bisogno
authors.forename: Rossella
authors.initials: R
authors.lastname: Sirianni
authors.forename: Vincenzo
authors.initials: V
authors.lastname: Di Marzo
mesh_terms: D000577:Amides / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D000581:Amidohydrolases / Q000378:metabolism; D000818:Animals; D001095:Arachidonic Acids / Q000378:metabolism; D001921:Brain / Q000378:metabolism; D002208:Caproates / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology; D002460:Cell Line; D000242:Cyclic AMP / Q000378:metabolism; D015195:Drug Design; D063388:Endocannabinoids; D005227:Fatty Acids / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D066298:In Vitro Techniques; D008024:Ligands; D026901:Membrane Transport Proteins / Q000378:metabolism; D010168:Palmitates / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology; D053284:Polyunsaturated Alkamides; D011869:Radioligand Assay; D051381:Rats; D043884:Receptor, Cannabinoid, CB1 / Q000819:agonists / Q000378:metabolism*; D043885:Receptor, Cannabinoid, CB2 / Q000378:metabolism*; D013154:Spleen / Q000378:metabolism; D013329:Structure-Activity Relationship; D000099252:Fatty Acid Amide Hydrolases
chemical_list: D000577:Amides; D000581:Amidohydrolases; D001095:Arachidonic Acids; D002208:Caproates; D000242:Cyclic AMP; D063388:Endocannabinoids; D005227:Fatty Acids; D008024:Ligands; D026901:Membrane Transport Proteins; D010168:Palmitates; D053284:Polyunsaturated Alkamides; D043884:Receptor, Cannabinoid, CB1; D043885:Receptor, Cannabinoid, CB2; D000099252:Fatty Acid Amide Hydrolases; C078814:anandamide