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QSAR Analysis of Δ8-THC Analogues:  Relationship of Side-Chain Conformation to Cannabinoid Receptor Affinity and Pharmacological Potency

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Research Triangle Institute, P.O. Box 12194, Research Triangle Park, North Carolina 27709-2194, Department of Pharmacology and Toxicology, MCV/VCU, Richmond, Virginia 23298, and Organix Inc., 240 Salem Street, Woburn, Massachusetts 01801
Cite this: J. Med. Chem. 2000, 43, 1, 59–70
Publication Date (Web):December 10, 1999
https://doi.org/10.1021/jm9902281
Copyright © 2000 American Chemical Society
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    Abstract

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    A novel quantitative structure−activity relationship (QSAR) for the side-chain region of Δ8-tetrahydrocannabinol (Δ8-THC) analogues is reported. A series of 36 side-chain-substituted Δ8-THCs with a wide range of pharmacological potency and CB1 receptor affinity was investigated using computational molecular modeling and QSAR analyses. The conformational mobility of each compound's side chain was characterized using a quenched molecular dynamics approach. The QSAR techniques included a modified active analogue approach (MAA), multiple linear regression analyses (MLR), and comparative molecular field analysis (CoMFA) studies. All three approaches yielded consistent results. The MAA approach applied to a set of alkene/alkyne pairs identified the most active conformers as those with conformational mobility constrained within an approximately 8 Å radius. MLR analyses (restricted to 15 hydrocarbon side-chain analogues) identified two variables describing side-chain length and terminus position that were able to fit the pharmacological data for receptor affinity with a correlation coefficient for pKD of 0.82. While chain length was found to be directly related to receptor affinity, the angle made by the side chain from its attachment point to its terminus (angle defined by C3−C1‘−side-chain terminus carbon, see Figure 1) was found to be inversely related to affinity. These results suggest that increased side-chain length and increased side-chain ability to wrap around the ring system are predicted to increase affinity. Therefore, the side chain's conformational mobility must not restrict the chain straight away from the ring system but must allow the chain to wrap back around toward the ring system. Finally, the CoMFA analyses involved all 36 analogues; they also provided data to support the hypothesis that for optimum affinity and potency the side chain must have conformational freedom that allows its terminus to fold back and come into proximity with the phenolic ring.

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    †

     Research Triangle Institute.

    §

     MCV/VCU.

    ‡

     Organix Inc.

    *

     Corresponding author. E-mail:  [email protected].

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    Pharmacological data for Δ8-THC side-chain analogues. This material is available free of charge via the Internet at http://pubs.acs.org.

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