![]() Their putative binding mode was analyzed using the recently resolved crystal structures of the hCB 1 receptor, (33, 34) shedding light on key structural features of the receptor binding site that are involved in ligand recognition and dissociation. The compounds show high affinities and a diverse range of kinetic profiles at the hCB 1 receptor, which allowed their structure–kinetic relationships (SKRs) to be established. ![]() (32) Selected compounds were progressed to a full competition association assay. (30, 31) Together with rimonabant, they were evaluated in a radioligand displacement assay, a GTPγS binding assay, and a dual-point competition association assay that enables the relatively fast kinetic screening of compounds. In the current study, we report the synthesis and evaluation of 1,2-diarylimidazol-4-carboxamide derivatives ( Figure 1d), as human CB 1 receptor antagonists with more polar characteristics than rimonabant. ![]() (27) The binding kinetics driven drug discovery approach for the hCB 1 receptor has been validated in some aspects already by its application in the development of allosteric modulators of the hCB 1 receptor. (23-26) By doing so, ligand–receptor interactions can be better understood, as together they not only comprise the equilibrium state of a ligand–receptor interaction but also its metastable intermediates and/or transition states. (20-22) In the research field of GPCRs, a number of structure–kinetic relationship (SKR) studies have been published and the results suggest that the strategic combination of SKR with classic structure–affinity relationships (SAR) can improve the resulting decision process. In particular, the receptor–ligand residence time (RT) is emerging as an additional parameter to assess the therapeutic potential of drug candidates with respect to drug efficacy and safety. (6-9)ĭrug target binding kinetic parameters are receiving increasing attention, alongside classical affinity ( K i) and potency (IC 50) values, as has been discussed for several other class A GPCRs. Furthermore, activation in the peripheral tissues contributes to energy balance and metabolic processes. (5, 6) The presence of the hCB 1 receptor within both the CNS and PNS mediates neurotransmitter release and controls various cognitive, motor, emotional, and sensory functions. ![]() (3) The hCB 1 receptor is present in the central nervous system (CNS) and is widely distributed in the peripheral nervous system (PNS) and peripheral tissues, (2, 4) including heart, liver, lung, gastrointestinal tract, pancreas, and adipose tissue. ![]() (1, 2) The hCB 1 and hCB 2 receptors show 44% overall sequence homology and display different pharmacological profiles. (1) They are members of the rhodopsin-like class A G-protein-coupled receptors (GPCRs) and are primarily activated by endogenous cannabinoids (endocannabinoids, ECs), including anandamide (or N-arachidonylethanolamine, AEA) and 2-arachidonoylglycerol (2-AG). Within the endocannabinoid system (ECS), two human cannabinoid receptor subtypes have been identified: the human CB 1 (hCB 1) receptor and the human CB 2 (hCB 2) receptor. ![]()
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