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 [3 H]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.
Research in the R.M. laboratory was supported by the Kessler Family Foundation and by National Institute on Drug Abuse Grant DA-9789.
- pose occupancy