The novel selective D1 dopaminergic full agonists A-68930, A-77636 were discovered by the synthesis of molecules to probe the bioactive conformation of the partial agonist SKF-38393, by the use of this information to add D1 affinity and selectivity to a screening hit, and by traditional medicinal chemistry exploration of structure-activity relationships. The subsequent design of A-86929 and ABT-413 capitalized on these results, recently disclosed agonists, and traditional medicinal chemistry. 1. Introduction For many years dopamine was considered to be biologically inert and acted merely as a precursor to the important neurotransmitters norepinephrine and dopamine [1]. However, Abbott’s research on the biological properties of dopamine started in the late 1950s after the discovery of the monoamine oxidase inhibitor pargyline [2–4]. Using this compound Dr. Guy Everett showed that dopamine is an important neurotransmitter—a fact that was not universally accepted in the early 1960s [5–8]. He described dopamine as “the Cinderella compound,” unappreciated but not to be overlooked [1]. Although the role of dopamine in Parkinsonism was understood at this time, this was not an area of active investigation at Abbott Laboratories. Instead, monoamine oxidase inhibitors were targeted to the treatment of depression. Somewhat later we had a small effort to discover an inhibitor of dopamine-β-hydroxylase, the enzyme that converts dopamine to norepinephrine [9]. Because norepinephrine raises blood pressure but dopamine does not, such compounds would be potential antihypertensives [10]. Although we had a robust QSAR, the project was abandoned before we found a novel inhibitor. A few years later Abbott had a joint project with Dr. Leon Goldberg from the University of Chicago. The objective was to design prodrugs of dopamine that would be selectively released in the kidney. Such agents would be useful in congestive heart failure and shock because they would not have the hemodynamic side effects of parenterally administered dopamine. They might be useful, at higher doses, as hypertensive agents [11, 12]. Our first prodrugs were alpha-amino acid amides of the amino group of dopamine. Although these prodrugs release dopamine in the kidney, the primary site of hydrolysis is the gut. Hence, they are not renalspecific [13, 14]. However, after a literature search we proposed the γ-glutamyl derivative. It is indeed released primarily in the kidney [15]. The compound was patented, but it was not developed further [16, 17]. The structure-activity relationships of these compounds
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