| Summary: | Part I We report the design, synthesis, and biochemical characterization of novel cannabinergic ligands with remarkably high binding affinities for cannabinoid receptors that has tight/irreversible binding characteristics. These molecular probes are currently being used in studies that aim to uncover the binding motifs of classical cannabinoids with CB1 and CB2 receptors by using two approaches: receptor crystallography and the Ligand Assisted Protein Structure (LAPS)
approach, which combines the use of receptor mutants and mass spectrometric proteomic analysis. Our ligand design relies on the incorporation of reactive groups at judiciously chosen positions within the classical cannabinoid structure, including the aliphatic chain at C3 and the substituents at C11. Reactive groups included the electrophilic isothiocyanate and photoactivatable azido moiety as well as the polar nitrate ester and cyano groups, all of which are capable of
tight/irreversible interactions with the target protein. Incorporation of one reactive group results in mono functional probes, while incorporation of two reactive groups leads to bifunctional ligands that can carry either a single reactive group (homo-bifunctional) or two different reactive groups (hetero-bifunctional). The novel probes behave as potent CB1 agonists as evidenced by functional data while a representative nitrate ester probe is a potent analgesic in mice. Part II The
interaction of plant derived (-)-Δ9-THC with CB1 and CB2 receptors may affect diverse features of mammalian (patho)physiology. Modulation the activity of these two receptors is therefore a very exciting pharmacotherapeutic approach for the treatment of an array of CNS and/or PNS related indications. Unfortunately, only a limited number of cannabinergic agents have been approved till date due to the poor pharmacokinetic/pharmacodynamic (PK/PD) properties as well as adverse psychotropic
side effects associated with CB1 receptor activation. In our work, methods for obtaining novel cannabinoid analogues with controllable-deactivation or controllable-activation and improved druggability have been developed. As one part of the design of controlled deactivation cannabinoids project, a new chemotype of cannabinol (CBN) analogues containing a seven-member lactone ring in the B-ring position have been disclosed. Our results show that certain lactone bearing compounds are good
binders towards both CB1 and CB2 receptors, while their hydrolysis products are all inactive. Another approach of improving drug delivery or pharmacokinetics is the design of prodrugs. Our novel gamma-hydroxybutyric acetic acid sodium salt AM11253 is inactive towards both CB receptors. However, it can undergo a spontaneous ring-closure reaction to form the active lactone analogue under an acidic pH. This property can be utilized to design pH mediated water-soluble
prodrug.
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