The long term goal of this research project is to elucidate the basis for the actions of cannabinoids (CBs) at the molecular level. To this end, we are developing the elements of an understanding of the relationships between cannabinoid ligand structure; cannabinoid receptor structure; and cannabinoid receptor activation at an atomic level of detail. I am applying for this KO2 award to enable me to reduce the amount of time I spend on teaching and services duties (currently at 50 percent). Under the plan detailed in this application, redirection of my responsibilities will enable me to devote 15 percent of my time to teaching and service and 85 percent of my time solely to research. Computational projects (such as the cannabinoid project in which I am engaged) are based upon experimental results reported in the literature or obtained through collaborative studies. It is critical, for me as a computational chemist, to understand experimental methodology and its pit-falls; to understand where problems of interpretation arise; and, to learn where differences in methodology may affect interpretation. In order to increase my knowledge base in this area, the Career Development Plan proposed here includes extended visits to the laboratories of Dr. Mary Abood (California Pacific Medical Center) and Dr. Dale Deutsch (SUNY-Stony Brook). During my visits, I will learn the techniques used in site-directed mutagenesis studies of the CB1 and CB2 receptors and the anandamide amidohydrolase enzyme. I plan to learn how affinities are measured; how functional assays are chosen and performed; and, how data is interpreted. The Career Development Plan also includes a computational chemistry component in which I will learn new receptor modeling techniques that include consideration of environment in the laboratory of Dr. Frank Guarnieri (Mt. Sinai School of Medicine). The computational projects which comprise the Research Plan in this application are aimed at developing a pharmacophore for endogenous cannabinoids; studying the interactions of agonists at the CB1 and CB2 receptors; and, studying the interaction of CB1/CB2 inverse agonists at their receptors. It is hoped that novel hypotheses concerning endogenous ligand/receptor interaction may provide insights into the nature of the interactions of endogenous CBs with other targets, including the anandamide amidase enzyme. The redistribution of my effort, combined with the training experience planned, will enhance my career in drug abuse research and hopefully will lead to new insights concerning the action of the cannabinoids at the molecular level.
| Pei, Ying; Mercier, Richard W; Anday, Jenine K et al. (2008) Ligand-binding architecture of human CB2 cannabinoid receptor: evidence for receptor subtype-specific binding motif and modeling GPCR activation. Chem Biol 15:1207-19 |
| Reggio, Patricia H (2006) Computational methods in drug design: modeling G protein-coupled receptor monomers, dimers, and oligomers. AAPS J 8:E322-36 |
| Lynch, Diane L; Reggio, Patricia H (2005) Molecular dynamics simulations of the endocannabinoid N-arachidonoylethanolamine (anandamide) in a phospholipid bilayer: probing structure and dynamics. J Med Chem 48:4824-33 |
| Singh, R; Hurst, D P; Barnett-Norris, J et al. (2002) Activation of the cannabinoid CB1 receptor may involve a W6 48/F3 36 rotamer toggle switch. J Pept Res 60:357-70 |
| Reggio, Patricia H (2002) Endocannabinoid structure-activity relationships for interaction at the cannabinoid receptors. Prostaglandins Leukot Essent Fatty Acids 66:143-60 |
