Dopamine D3 receptor agonists as pharmacological tools.

Dysregulation of the dopaminergic innervation in the central nervous system plays a key role in different neurological disorders like Parkinson´s disease, restless legs syndrome, schizophrenia etc. Although dopamine D3 receptors have been recognized as an important target in these diseases, their full pharmacological properties need further investigations. With focus on dopamine D3 receptor full agonists, this review has divided the ergoline and non-ergoline ligands in dissimilar chemical subclasses describing their pharmacodynamic properties on different related receptors, on species differences and their functional properties on different signaling mechanism. This is combined with a short description of structure-activity relationships for each class. Therefore, this overview should support the rational choice for the optimal compound selection based on affinity, selectivity and efficacy data in biochemical and pharmacological studies.

Piperazine modification in 2,4,6-triaminopyrimidine derivatives as histamine H4 receptor ligands.

The human histamine H4 receptor (hH4R) is a promising new target in the therapy of inflammatory and immunomodulatory diseases. The 2,4,6-triaminopyrimidine structure has been established as a potent hH4R affinity scaffold. By using the inverse agonist ST-1012 as reference ligand, piperazine modifications were performed to get larger structural variations. Therefore, different spacers were introduced into the lead structure and the influence on affinity of this basic element was evaluated. While a short distance between aminopyrimidine and basic moiety is beneficial, a lipophilic group in the eastern part is necessary to maintain hH4R affinity.