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Structure–Activity Relationships and Conformational Freedom of CB1 Receptor Antagonists and Inverse Agonists

  • Chapter
The Cannabinoid Receptors

Part of the book series: The Receptors ((REC))

Abstract

In the last few decades, our knowledge of cannabinoid structure–activity relationships (SARs) has increased dramatically. Computational methods have allowed us to compare active and inactive ligands for steric, electronic, and conformational similarities and dissimilarities. Knowing that there are specific G-protein-coupled cannabinoid receptors with which cannabinoids interact, we increasingly interpret changes in structure to specific alterations in ligand–receptor interaction. With additional knowledge of the CB1 and CB2 receptors’ sequence, the consequences of mutations and chimeric constructs of the receptor, and the development of rhodopsin-based homology models of the cannabinoid receptors, we continue to gain insight into the interaction of cannabinoids with their receptors. Finally, our emerging appreciation for cannabinoid homo- and heterodimerization/oligomerization provides for further understanding of ligand–receptor interactions, the interaction of receptors with each other, and the interaction of G-protein-coupled receptors with their signal transduction components and other molecules affecting each receptor’s dynamics. In the following review, we have attempted to characterize the emerging SARs of an important class of cannabinoid ligands: the CB1 receptor antagonists and inverse agonists. This class of compounds is showing therapeutic potential for a variety of indications, and is therefore of interest for both basic research and pharmaceutical development. Throughout this work, we have used molecular modeling, particularly quenched molecular dynamics, to illustrate particular structural modifications that have been reported for CB1 antagonists, their conformational properties, and the potential implications for receptor interaction. In this way, we hope this review serves to further guide medicinal chemists in their understanding of CB1 receptor antagonist SAR and the design of new analogs.

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Acknowledgments

The authors would like to acknowledge the financial support received from the National Institute on Drug Abuse (R01 DA019217).

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  1. RTI International, PO Box 12194, 3040 Cornwallis Road, Research Triangle Park, NC 27709-2194, USA

    Brian F. Thomas

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  1. Yanan Zhang
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  2. Herbert H. Seltzman
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  3. Marcus Brackeen
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Correspondence to Brian F. Thomas .

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  1. University of North Carolina, Greensboro, NC, USA

    Patricia H. Reggio

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Zhang, Y., Seltzman, H.H., Brackeen, M., Thomas, B.F. (2009). Structure–Activity Relationships and Conformational Freedom of CB1 Receptor Antagonists and Inverse Agonists. In: Reggio, P.H. (eds) The Cannabinoid Receptors. The Receptors. Humana Press. https://doi.org/10.1007/978-1-59745-503-9_4

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