( R)- N-(1-Methyl-2-hydroxyethyl)-13-( S)-methyl-arachidonamide (AMG315): A Novel Chiral Potent Endocannabinoid Ligand with Stability to Metabolizing Enzymes.

The synthesis of potent metabolically stable endocannabinoids is challenging. Here we report a chiral arachidonoyl ethanolamide (AEA) analogue, namely, (13 S,1' R)-dimethylanandamide (AMG315, 3a), a high affinity ligand for the CB1 receptor ( K of 7.8 ± 1.

Novel 1',1'-chain substituted hexahydrocannabinols: 9β-hydroxy-3-(1-hexyl-cyclobut-1-yl)-hexahydrocannabinol (AM2389) a highly potent cannabinoid receptor 1 (CB1) agonist.

In pursuit of a more detailed understanding of the structural requirements for the key side chain cannabinoid pharmacophore, we have extended our SAR to cover a variety of conformationally modified side chains within the 9-keto and 9-hydroxyl tricyclic structures. Of the compounds described here, those with a seven-atom long side chain substituted with a cyclopentyl ring at C1' position have very high affinities for both CB1 and CB2 (0.97 nM < K(i) < 5.

Design and synthesis of (13S)-methyl-substituted arachidonic acid analogues: templates for novel endocannabinoids.

Two novel methyl-substituted arachidonic acid derivatives were prepared in an enantioselective manner from commercially available chiral building blocks, and were found to be excellent templates for the development of (13S)-methyl-substituted anandamide analogues. One of the compounds synthesized, namely, (13S,5Z,8Z,11Z,14Z)-13-methyl-eicosa-5,8,11,14-tetraenoic acid N-(2-hydroxyethyl)amide, is an endocannabinoid analogue with remarkably high affinity for the CB1 cannabinoid receptor.

Cannabilactones: a novel class of CB2 selective agonists with peripheral analgesic activity.

The identification of the CB2 cannabinoid receptor has provided a novel target for the development of therapeutically useful cannabinergic molecules. We have synthesized benzo[ c]chromen-6-one analogs possessing high affinity and selectivity for this receptor. These novel compounds are structurally related to cannabinol (6,6,9-trimethyl-3-pentyl-6 H-benzo[ c]chromen-1-ol), a natural constituent of cannabis with modest CB2 selectivity.

Combined 3D QSAR and molecular docking studies to reveal novel cannabinoid ligands with optimum binding activity.

The combination of NMR spectroscopy and molecular modeling studies provided the putative bioactive conformation for the analgesic cannabinoid (CB) ligand (-)-2-(6a,7,10,10a-tetrahydro-6,6,9-trimethylhydroxy-6H-dibenzo[b,d]pyranyl)-2-hexyl 1,3-dithiolane which served as a template in reported three-dimensional quantitative structure-activity relationship (3D QSAR) studies [Durdagi et al., J. Med.

C1'-cycloalkyl side chain pharmacophore in tetrahydrocannabinols.

In earlier work we have provided evidence for the presence of a subsite within the CB1 and CB2 cannabinoid receptor binding domains of classical cannabinoids. This putative subsite corresponds to substituents on the C1'-position of the C3-alkyl side chain, a key pharmacophoric feature in this class of compounds. We have now refined this work through the synthesis of additional C1'-cycloalkyl compounds using newly developed approaches.

The application of 3D-QSAR studies for novel cannabinoid ligands substituted at the C1' position of the alkyl side chain on the structural requirements for binding to cannabinoid receptors CB1 and CB2.

A set of 30 novel Delta8-tetrahydrocannabinol and cannabidiol analogues were subjected to three-dimensional quantitative structure-activity relationship studies using the comparative molecular field analysis (CoMFA) and comparative molecular similarity indices analysis (CoMSIA) approaches. Using a combination of molecular modeling techniques and NMR spectroscopy, the putative bioactive conformation of the most potent cannabinoid (CB) ligand in the training set was determined. This conformer was used as the template and CB1 and CB2 pharmacophore models were developed.

Mapping the melatonin receptor. 7. Subtype selective ligands based on beta-substituted N-acyl-5-methoxytryptamines and beta-substituted N-acyl-5-methoxy-1-methyltryptamines.

A series of beta-substituted and beta,beta-disubstituted N-acyl 5-methoxy-1-methyltryptamines and 5-methoxytryptamines have been prepared as melatonin analogues to investigate the nature of the binding site of the melatonin receptor. The affinity of analogues was determined in a radioligand binding assay using cloned human MT(1) and MT(2) receptor subtypes expressed in NIH 3T3 cells. Agonist and antagonist potency of all analogues was measured using the pigment aggregation response of a clonal line of Xenopus laevis melanophores.

Structural modifications of the cannabinoid side chain towards C3-aryl and 1',1'-cycloalkyl-1'-cyano cannabinoids.

The compounds reported in this study are Delta(8)-THC analogues in which the C3 five-carbon linear side chain of Delta(8)-THC was replaced with aryl and 1',1'-cycloalkyl substituents. Of the compounds described here analogues 2d (CB(1), K(i)=11.7 nM.

The role of halogen substitution in classical cannabinoids: a CB1 pharmacophore model.

The presence of halogens within the classical cannabinoid structure leads to large variations in the compounds' potencies and affinities for the CB1 receptors. To explore the structure activity relationships within this class of analogs we have used a series of halogen-substituted (-)-Delta8-tetrahydrocannabinol analogs and compared their affinities for the CB1 cannabinoid receptor. Our results indicate that halogen substitution at the end-carbon of the side chain leads to an enhancement in affinity with the bulkier halogens (Br, I) producing the largest effects.

Pharmacophoric requirements for the cannabinoid side chain. Probing the cannabinoid receptor subsite at C1'.

Earlier work from our laboratories has provided evidence for the existence of a subsite within the CB1 and CB2 cannabinoid receptor binding domain corresponding to substituents at the benzylic side chain position of classical cannabinoids. The existence and stereochemical features of this subsite have now been probed through the synthesis of a novel series of (-)-Delta(8)-tetrahydrocannabinol analogues bearing C1'-ring substituents. Of the compounds described here, those with C1'-dithiolane (1c), C1'-dioxolane (2d), and cyclopentyl (2a) substituents exhibited the highest affinities for CB1 and CB2.

Novel 1',1'-chain substituted Delta(8)-tetrahydrocannabinols.

1',1'-Cyclopropyl side chain substituents enhance the affinities of Delta(8)-tetrahydrocannabinol and respective cannabidiol analogues for the CB1 and CB2 cannabinoid receptors. The results support the hypothesis for a subsite within CB1 and CB2 binding domain at the level of the benzylic side chain carbon in the tetrahydrocannabinol and cannabidiol series. Efficient procedures for the synthesis of 1',1'-cyclopropyl analogues are described.