Neuroscience 2004 Abstract
| Presentation Number: | 961.14 |
|---|---|
| Abstract Title: | <I>in vitro</I> characterization of structural analogs of a biaryl cannabinoid mimetic.<I> |
| Authors: |
Stabley, G. J.*1
; Dolle, R. E.1
; Worm, K.1
; Zhou, Q. J.1
; DeHaven, R. N.1
1Dept of Molec Pharmacol, Adolor corp, Exton, PA |
| Primary Theme and Topics |
Synaptic Transmission and Excitability - G-Protein linked Receptors -- Other |
| Session: |
961. GPCR-Linked Receptors: Other Poster |
| Presentation Time: | Wednesday, October 27, 2004 2:00 PM-3:00 PM |
| Location: | San Diego Convention Center - Hall A-H, Board # N5 |
| Keywords: | CANNABINOID |
The biaryl cannabinoid mimetic reported by Gareau, et al. (Bioorg Med Chem Lett 6:189, 1996), and shown by us to have potent antihyperalgesic activity in the Freund’s complete adjuvant-induced hyperalgesia assay in the rat (Stabley, et al. Program No. 578.9. Abstract Viewer/Itinerary Planner SfN, 2003), is a valuable lead compound to explore the structure activity relationships at the human cannabinoid CB1 and CB2 receptors. The biaryl lead compound, although being nonselective in its binding profile and its activation of the hCB receptors, provided a starting point for the synthesis of new analogs with substitutions on the top aryl ring. We tested these analogs for their ability to inhibit [3H]CP55940 binding to cloned human CB1 and CB2 receptors expressed in Chinese hamster ovary cells, as well as for their abilities to stimulate [35S]GTPγS binding mediated by these receptors. Binding affinities of the analogs ranged from ca. 1.0 nM to > 1000 nM without dramatic divergence in the SAR profiles for the two receptors. Para substitution, in general, reduced potencies by about 2 orders of magnitude. Bulkier substituents, such as isopropyl, were not well tolerated in the ortho position. Some polar character was also tolerated in the meta position, e.g., methylsulfonamide. All of the compounds behaved as full agonists in the [35S]GTPγS assay with potencies consistent with their binding affinities. Activity for both hCB receptors is retained when the top aryl ring is substituted in the meta and/or ortho positions, but it is not conserved when a para substituent is provided.
<B>Conflict of Interest:</B> Authors have an equity position in the company
Sample Citation:
[Authors]. [Abstract Title]. Program No. XXX.XX. 2004 Neuroscience Meeting Planner. San Diego, CA: Society for Neuroscience, 2004. Online.
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