3-(2-Amino-4-methylthiazol-5-yl)propyl-substituted carbamoylguanidines are potent, subtype-selective histamine H 2 receptor (H 2 R) agonists, but their applicability as pharmacological tools to elucidate the largely unknown H 2 R functions in the central nervous system (CNS) is compromised by their concomitant high affinity toward dopamine D 2 -like receptors (especially to the D 3 R). To improve the selectivity, a series of novel carbamoylguanidinetype 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 H 2 -and D 2long/3 -receptors. These results provide a solid base for the exploration of the H 2 R functions in the brain in further studies.