Title

Novel cannabinergic agents and molecular probes

Date of Completion

January 2005

Keywords

Biology, Molecular|Chemistry, Organic|Health Sciences, Pharmacy

Degree

Ph.D.

Abstract

The objectives of this study were to identify the structural determinants for selective recognition of the CB1 and CB2 cannabinoid receptors, to develop fluorescent ligands and photoactivable covalent ligands for the cannabinoid receptors, and to develop water-soluble cannabinergic molecules. Natural products, (-)-Δ8-tetrahydrocannabinol, cannabinol, and cannabinodiol were employed as molecular templates for the design and synthesis of these novel molecular probes and cannabinergic molecules. Ten series of cannabimimetic compounds were synthesized in this study. ^ Two strategies were identified within the structures of classical cannabinoids for the improvement of the binding selectivity for the CB2 receptors. First, conformational restriction of the C3 substituents of classical cannabinoids led to remarkable selectivity for both mouse and human CB2 receptors. Second, replacing the C6-dimethyl groups of cannabinol with a carbonyl group significantly increased the selectivity for the mouse CB2 receptors. However, species differences between the mouse CB2 and the human CB2 receptors were observed from our competitive binding assays using this class of compounds. ^ The structural hybrids of coumarins and classical cannabinoids led to the discovery of the first type of intrinsically fluorescent cannabinoids. This class of molecular probes will serve as valuable tools for exploring the endocannabinoid system. ^ Our novel approach for the synthesis of 3-amino-cannabinoids established a highly efficient method for the synthesis of classical cannabinoids, which typically requires tedious work to connect the C3 substituent with the phenyl ring of the tricyclic structure. Forming ammonium salts within the structures of certain 3-amino-cannabinoids generated a group of water-soluble cannabinergic molecules. ^ The structure-activity relationship obtained from the Δ 8-tetrahydrocannabinol analogs revealed that the active sites of CB1 and CB2 receptors can tolerate bulky groups placed in the close proximity of the phenolic ring of classical cannabinoids. However, the active sites of CB1 and CB2 receptors have different requirements for the size and conformation of the C3 bulky substituents of classical cannabinoids. This indicated that the subsites of CB1 and CB2 receptors for accommodating the side chains of classical cannabinoids are significantly different in volume and orientation. ^