Giorgio Bertolini

Perspectives in the design and application of dopamine receptor agonists

Publisher Summary This chapter discusses the perspectives in the design and application of dopamine receptor agonists. The chapter discusses main pharmacological and clinical achievements as well as the essential results of the search of pharmacophores and of tentative receptor models, to provide the basis for understanding “third generation” of dopamine receptor agonists. The era of dopamine receptor pharmacology began around 1960. Heralded by the discovery of the neurotransmitter role of dopamine, it was previously regarded only as a metabolic precursor of noradrenaline. A new avenue of investigation of the interactions of agonistic and antagonistic ligands with receptor models directly derived from the structure of the protein is opened by recent advancements. Thus, progress in indirect modeling, based on steric and electronic properties of the ligands, plays an important role not only in the design of new active compounds, but also in the improvement and the validation of the direct models. In these models, it has been generally accepted that at least one phenolic or equivalent function, such as the indole NH group of the ergolines, acts as a hydrogen bond donor with respect to a site of the receptor. The recent discovery of potent dopamine agonists devoid of such functions suggests that recognition modes other than hydrogen bonding may be involved in the corresponding region of the receptor.