Synthesis and pharmacological evaluation of 1-(aminomethyl)-3,4-dihydro-5-hydroxy-1H-2-benzopyrans as dopamine D1 selective ligands

• Published in: Journal of medicinal chemistry 1991-10, Vol.34 (10), p.2946-2953
• Main Authors: Michaelides, Michael R, Schoenleber, Robert, Thomas, Sheela, Yamamoto, Diane M, Britton, Donald R, MacKenzie, Robert, Kebabian, John W
• Format: Article
• Language: English
• Subjects: Adenylyl Cyclase Inhibitors; Chemistry; Chromans - chemical synthesis; Chromans - metabolism; Chromans - pharmacology; Dopamine - pharmacology; Dopamine Antagonists; Exact sciences and technology; Heterocyclic compounds; Heterocyclic compounds with o, s, se, te hetero atom and condensed derivatives; Molecular Structure; Organic chemistry; Preparations and properties; Receptors, Dopamine - metabolism; Receptors, Dopamine D1; Receptors, Dopamine D2; Structure-Activity Relationship
• ISSN: 0022-2623; 1520-4804
• DOI: 10.1021/jm00114a002

A series of 3-substituted 1-(aminomethyl)-3,4-dihydro-5-hydroxy-1H-2- benzopyrans were prepared as potential D1 selective antagonists. The compounds were evaluated for their affinity and selectivity for the D1 receptor as well as for their functional antagonism of D1-mediated pharmacological events. The compounds show potent D1 antagonist properties in vitro. The optimum nitrogen substitution was found to be the primary amine and the observed order of potency for substitution at the 6-position is OH greater than Br greater than H greater than OMe. Two representative compounds, the 6-methyl and 6-bromo analogues, were also evaluated in vivo for dopaminergic activity. Interestingly, both compounds behave as potent in vivo agonists.