Abstract
Differences in sequence homology between human (h), mouse (m), and rat (r) histamine H-4 receptors (H4R) cause discrepancies regarding affinities, potencies, and/or efficacies of ligands and therefore compromise translational animal models and the applicability of radioligands. Aiming at a radioligand enabling robust and comparative binding studies at the h/m/rH(4)Rs, 2,4-diaminopyrimidines were ...
Abstract
Differences in sequence homology between human (h), mouse (m), and rat (r) histamine H-4 receptors (H4R) cause discrepancies regarding affinities, potencies, and/or efficacies of ligands and therefore compromise translational animal models and the applicability of radioligands. Aiming at a radioligand enabling robust and comparative binding studies at the h/m/rH(4)Rs, 2,4-diaminopyrimidines were synthesized and pharmacologically investigated. The most notable compounds identified were two (partial) agonists with comparable potencies at the h/m/rH(4)Rs: UR-DEBa148 (N-neopentyl-4-(1,4,6,7-tetrahydro-5H-imidazo[4,5-c]pyridin-5-yl)pyrimidin-2-amine bis(2,2,2-trifluoroacetate), 43), the most potent [pEC(50) (reporter gene assay) = 9.9/9.6/10.3] compound in the series being slightly G-protein biased and UR-DEBa176 [(R)-4-[3-(dimethylamino)pyrrolidin-1-yl]-N-neopentylpyrimidin-2-amine bis(2,2,2-trifluoroacetate), 46, pEC(50) (reporter gene assay) = 8.7/9.0/9.2], a potential "cold" form of a tritiated H4R ligand. After radiolabeling, binding studies with [3H]UR-DEBa176 ([H-3]46) at the h/m/rH(4)Rs revealed comparable K-d values (41/17/22 nM), low nonspecific binding (11-17%, similar to K-d), and fast associations/dissociations (25-30 min) and disclosed [H-3]UR-DEBa176 as useful molecular tool to determine h/m/rH(4)R binding affinities for H4R ligands.
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