Bicyclic and tricyclic ergoline partial structures. Rigid 3-(2-aminoethyl)pyrroles and 3- and 4-(2-aminoethyl)pyrazoles as dopamine agonists

• Published in: Journal of medicinal chemistry Vol. 23; no. 5; pp. 481 - 491
• Main Authors: Bach, Nicholas J, Kornfeld, Edmund C, Jones, Noel D, Chaney, Michael O, Dorman, Douglas E, Paschal, Jonathan W, Clemens, James A, Smalstig, E. Barry
• Format: Journal Article
• Language: English
• Published: United States American Chemical Society 01.05.1980
• Subjects: Animals; Chemical Phenomena; Chemistry; Dopamine - physiology; Ergolines - chemical synthesis; Humans; Models, Molecular; Molecular Conformation; Prolactin - antagonists & inhibitors; Prolactin - blood; Pyrazoles - chemical synthesis; Pyrazoles - pharmacology; Pyrroles - chemical synthesis; Pyrroles - pharmacology; Rats; Stereotyped Behavior - drug effects
• ISSN: 0022-2623; 1520-4804
• DOI: 10.1021/jm00179a003

It is proposed, based upon comparisons with apomorphine, that the rigid pyrroleethylamine moiety of the ergolines is the portion of the molecule responsible for dopamine agonist activity. In support of this hypothesis, bicyclic and tricyclic ergoline partial structures 6, 11, 25, and 35 have been synthesized. In addition, some pyrazole isosters (37, 38, 40, and 45) of these rigid pyrroleethylamines have been made. All of the classes show dopaminergic activity in prolactin inhibition and in lesioned rat turning assays. The most potent drugs, the linear tricyclic pyrazoles 38 (R = Pr) and 40 (R = Pr), are comparable in potency with the highly active ergoline pergolide (41).