Abolishing Dopamine D/D Receptor Affinity of Subtype-Selective Carbamoylguanidine-Type Histamine H Receptor Agonists.

3-(2-Amino-4-methylthiazol-5-yl)propyl-substituted carbamoylguanidines are potent, subtype-selective histamine H receptor (HR) agonists, but their applicability as pharmacological tools to elucidate the largely unknown HR functions in the central nervous system (CNS) is compromised by their concomitant high affinity toward dopamine D-like receptors (especially to the DR). 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 and D receptors. This study revealed a couple of selective candidates (among others and ), 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- and D-receptors. These results provide a solid base for the exploration of the HR functions in the brain in further studies.