Abolishing Dopamine D_2long/D₃ Receptor Affinity of Subtype-Selective Carbamoylguanidine-Type Histamine H₂ Receptor...

3-(2-Amino-4-methylthiazol-5-yl)propyl-substituted carbamoylguanidines are potent, subtype-selective histamine H₂ receptor (H₂R) agonists, but their applicability as pharmacological tools to elucidate the largely unknown H₂R functions in the central nervous system (CNS) is compromised by their concomitant high affinity toward dopamine D₂-like receptors (especially to the D₃R). To improve the selectivity, a series of novel carbamoylguanidine-type ligands containing various heterocycles, spacers, and side residues were rationally designed, synthesized, and tested in binding and/or functional assays at H_1-4 and D_2long/3 receptors. This study revealed a couple of selective candidates (among others 31 and 47), and the most promising ones were screened at several off-target receptors, showing good selectivities. Docking studies suggest that the amino acid residues (3.28, 3.32, E2.49, E2.51, 5.42, and 7.35) are responsible for the different affinities at the H₂- and D_2long/3-receptors. These results provide a solid base for the exploration of the H₂R functions in the brain in further studies.