Pharmacological characterization of a new series of carbamoylguanidines reveals potent agonism at the HR and DR.

Even today, the role of the histamine H receptor (HR) in the central nervous system (CNS) is widely unknown. In previous research, many dimeric, high-affinity and subtype-selective carbamoylguanidine-type ligands such as UR-NK22 (5, pK = 8.07) were reported as HR agonists. However, their applicability to the study of the HR in the CNS is compromised by their molecular and pharmacokinetic properties, such as high molecular weight and, consequently, a limited bioavailability. To address the need for more drug-like HR agonists with high affinity, we synthesized a series of monomeric (thio)carbamoylguanidine-type ligands containing various spacers and side-chain moieties. This structural simplification resulted in potent (partial) agonists (guinea pig right atrium, [S]GTPγS and β-arrestin2 recruitment assays) with human (h) HR affinities in the one-digit nanomolar range (pK (139, UR-KAT523): 8.35; pK (157, UR-MB-69): 8.69). Most of the compounds presented here exhibited an excellent selectivity profile towards the hHR, e.g. 157 being at least 3800-fold selective within the histamine receptor family. The structural similarities of our monomeric ligands to pramipexole (6), a dopamine receptor agonist, suggested an investigation of the binding behavior at those receptors. The target compounds were (partial) agonists with moderate affinity at the hDR and agonists with high affinity at the hDR (e.g. pK (139, UR-KAT523): 7.80; pK (157, UR-MB-69): 8.06). In summary, we developed a series of novel, more drug-like HR and DR agonists for the application in recombinant systems in which either the HR or the DR is solely expressed. Furthermore, our ligands are promising lead compounds in the development of selective HR agonists for future in vivo studies or experiments utilizing primary tissue to unravel the role and function of the HR in the CNS.