α2-Adrenoceptor Antagonists: Synthesis, Pharmacological Evaluation, and Molecular Modeling Investigation of Pyridinoguanidine, Pyridino-2-aminoimidazoline and Their Derivatives

We have previously identified phenylguanidine and phenyl-2-aminoimidazoline compounds as high affinity ligands with conflicting functional activity at the alpha(2)-adrenoceptor, a G-protein-coupled receptor with relevance in several neuropsychiatric conditions. In this paper we describe the design, synthesis, and pharmacological evaluation of a new series of pyridine derivatives [para substituted 2- and 3-guanidino and 2- and 3-(2-aminoimidazolino)pyridines, disubstituted 2-guanidinopyridines and N-substituted-2-amino-1,4-dihydroquinazolines] that were found to be antagonists/inverse agonists of the alpha(2)-adrenoceptor. Furthermore, the compounds exert their effects at the alpha(2)-adrenoceptor both in vitro in human prefrontal cortex tissue and in vivo in rat brain as shown by microdialysis experiments. We also provide a docking study at the alpha(2A)- and alpha(2C)-adrenoceptor subtypes demonstrating the structural features required for high affinity binding to the receptor.