Conformational characteristics of the interaction of SR141716A with the CB1 cannabinoid receptor as determined through the use of conformationally constrained analogs

Abstract

Interest in cannabinoid pharmacology increased dramatically upon the identifi cation of the fi rst cannabinoid receptor (CB1) in 1998 and continues to expand as additional endocannabinoids and cannabinoid receptors are discovered. Using CB1 receptor (CB1R) systems, medicinal chemistry programs began screening libraries searching for cannabinoid ligands, ultimately leading to the discovery of the fi rst potent cannabinoid receptor antagonist, SR141716A (Rimonabant). Its demonstrated effi cacy in treating obesity and facilitating smoking cessation, among other impressive pharmacological activities, has furthered the interest in cannabinoid receptor antagonists as therapeutics, such that the number of patents and publications covering this class of compounds continues to grow at an impressive rate. At this time, medicinal chemistry approaches including combinatorial chemistry, conformational constraint, and scaffold hopping are continuing to generate a large number of cannabinoid antagonists. These molecules provide an opportunity to gain insight into the 3-dimensional structure-activity relationships that appear crucial for CB1R-ligand interaction. In particular, studies in which conformational constraints have been imposed on the various pyrazole ring substituents of SR141716A provide a direct opportunity to characterize changes in conformation/ conformational freedom within a single class of compounds. While relatively few conformationally constrained molecules have been synthesized to date, the structureactivity information is often more readily interpreted than in studies where entire substituents are replaced. Thus, it is the focus of this mini-review to examine the structural properties of SR141716A, and to use conformationally constrained molecules to illustrate the importance of conformation and conformational freedom to CB1R affi nity, selectivity, and effi cacy.

<p>Role of pseudohypoxia in the pathogenesis of type 2 diabetes</p>

“…This study clearly demonstrates that NR supplementation can restore NADH/NAD redox balance by increasing cellular and tissue NAD contents 89. It should also be pointed out that as NAD can be synthesized de novo from either aspartic acid in bacteria or tryptophan in animals,93,94 the supplement of these substrates and enhancement of the pertinent enzymes involved in NAD synthesis can also be explored to fight pseudohypoxia in diabetes by boosting NAD content 95–98…”

Novel selective cannabinoid CB1 receptor antagonist MJ08 with potent in vivo bioactivity and inverse agonistic effects

“…When considering the cannabinoid CB 1 receptor to be a well-defined but dynamic receptor protein, changes in the receptor steric conformation under different circumstances will likely affect its response to exogenous ligands. Secondly, the complex pharmacological regulations depend on the particular profile of the used ligand; the minute difference in structure of MJ08 may be key because the compound's conformation or conformational freedom is crucial for the receptor's affinity, selectivity, and efficacy [33] . Different small-molecule antagonists and inverse agonists bind in very different modes into the funnel of the main ligand-binding pocket GPCRs.…”

The Potential for Clinical Use of Cannabinoids in Treatment of Cardiovascular Diseases

“…While it may seem that the cardioprotective effect of PEA and 2‐AG are mediated by CB2 receptor, selective CB 1 and CB 2 agonists receptors, ACEA and JWH‐015, respectively, reduced infarct size. This indicates that both CB1 and CB2 receptors, depending on the particular pharmacologic properties of the compound, may have a cardioprotective role [42,43]. Contrary to the results of the study by Phillipe [39], a subsequent study by Underdown et al was successful at demonstrating a cardioprotective effect for anandamide in an isolated heart model.…”