ISSN:
1471-4159
Source:
Blackwell Publishing Journal Backfiles 1879-2005
Topics:
Medicine
Notes:
Abstract: 3-Azidophenyl- and 3-isothiocyanatophenyl- and 2-(5′-azidopentyl)- and 2-(5′-isothiocyanatopentyl)pyrazoles were synthesized to determine whether these compounds could behave as covalently binding ligands for the CB1 cannabinoid receptor in rat brain membranes. Heterologous displacement of [3H]CP55940 indicated that the apparent affinity of these compounds for the CB1 receptor was similar to that of the parent compound, SR141716A, with the exception of the 3-isothiocyanato derivatives, which showed a 10-fold loss of affinity. The 3-azidophenyl and 3-isothiocyanatophenyl compounds behaved as antagonists against the cannabinoid agonist desacetyllevonantradol in activation of G proteins [guanosine 5′-O-(γ-35S]thio)triphosphate ([35S]GTPγS) binding] and regulation of adenylyl cyclase. The 2-(5′-azidopentyl)- and 2-(5′-isothiocyanatopentyl)pyrazoles were poor antagonists for [35S]GTPγS binding, and both compounds failed to antagonize the cannabinoid regulation of adenylyl cyclase. After incubation with the isothiocyanato analogues or UV irradiation of the azido analogues, the 3-substituted aryl pyrazoles formed covalent bonds with the CB1 receptor as evidenced by the loss of specific binding of [3H]CP55940. In the case of the isothiocyanato analogues, the log concentration-response curve for cannabinoid-stimulated [35S]GTPγS binding was shifted to the right, indicating that loss of receptors compromised signal transduction capability. These irreversibly binding antagonists might be useful tools for the investigation of tolerance and receptor down-regulation in both in vitro and in vivo studies.
Type of Medium:
Electronic Resource
URL:
http://dx.doi.org/10.1046/j.1471-4159.2000.0742174.x
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