CB2 cannabinoid receptor agonist enantiomers HU-433 and HU-308: An inverse relationship between binding affinity and biological potency

Activation of the CB2 receptor is apparently an endogenous protective mechanism. Thus, it restrains inflammation and protects the skeleton against age-related bone loss. However, the endogenous cannabinoids, as well as Δ⁹-tetrahydrocannabinol, the main plant psychoactive constituent, activate both c...

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Published in:Proceedings of the National Academy of Sciences - PNAS 2015-07, Vol.112 (28), p.8774-8779
Main Authors: Smoum, Reem, Baraghithy, Saja, Chourasia, Mukesh, Breuer, Aviva, Mussai, Naama, Attar-Namdar, Malka, Kogan, Natalya M., Raphael, Bitya, Bolognini, Daniele, Cascio, Maria G., Marini, Pietro, Pertwee, Roger G., Shurki, Avital, Mechoulam, Raphael, Bab, Itai
Format: Article
Language:English
Subjects:
Animals
Binding sites
Biological Sciences
Bones
Cannabinoid Receptor Agonists - chemistry
Cannabinoid Receptor Agonists - metabolism
Cannabinoid Receptor Agonists - pharmacology
Cannabinoids - chemistry
Cannabinoids - metabolism
Cannabinoids - pharmacology
Cell culture
CHO Cells
Cricetinae
Cricetulus
Mice
Mice, Inbred C57BL
Receptor, Cannabinoid, CB2 - agonists
Rodents
Stereoisomerism
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Summary:Activation of the CB2 receptor is apparently an endogenous protective mechanism. Thus, it restrains inflammation and protects the skeleton against age-related bone loss. However, the endogenous cannabinoids, as well as Δ⁹-tetrahydrocannabinol, the main plant psychoactive constituent, activate both cannabinoid receptors, CB1 and CB2. HU-308 was among the first synthetic, selective CB2 agonists. HU-308 is antiosteoporotic and antiinflammatory. Here we show that the HU-308 enantiomer, designated HU-433, is 3–4 orders of magnitude more potent in osteoblast proliferation and osteoclast differentiation culture systems, as well as in mouse models, for the rescue of ovariectomy-induced bone loss and ear inflammation. HU-433 retains the HU-308 specificity for CB2, as shown by its failure to bind to the CB1 cannabinoid receptor, and has no activity in CB2-deficient cells and animals. Surprisingly, the CB2 binding affinity of HU-433 in terms of [³H]CP55,940 displacement and its effect on [35S]GTPγS accumulation is substantially lower compared with HU-308. A molecular-modeling analysis suggests that HU-433 and -308 have two different binding conformations within CB2, with one of them possibly responsible for the affinity difference, involving [35S]GTPγS and cAMP synthesis. Hence, different ligands may have different orientations relative to the same binding site. This situation questions the usefulness of universal radioligands for comparative binding studies. Moreover, orientation-targeted ligands have promising potential for the pharmacological activation of distinct processes.
ISSN:0027-8424
1091-6490
DOI:10.1073/pnas.1503395112