Synthesis of 4-substituted 2H-naphth[1,2-b]-1,4-oxazines, a new class of dopamine agonists

• Published in: Journal of medicinal chemistry 1984-12, Vol.27 (12), p.1607-1613
• Main Authors: Jones, James H, Anderson, Paul S, Baldwin, John J, Clineschmidt, Bradley V, McClure, David E, Lundell, George F, Randall, William C, Martin, Gregory E, Williams, Michael
• Format: Article
• Language: English
• Subjects: Animals; Apomorphine - metabolism; Cattle; Cerebral Cortex - metabolism; Chemistry; Clonidine - metabolism; Dopamine - analogs & derivatives; Exact sciences and technology; Heterocyclic compounds; Heterocyclic compounds with n hetero atom and also o and/or s, se, te hetero atoms; Hydroxydopamines - pharmacology; Indicators and Reagents; Models, Molecular; Molecular Conformation; Motor Activity - drug effects; Organic chemistry; Oxazines - chemical synthesis; Oxazines - pharmacology; Oxidopamine; Preparations and properties; Rats; Receptors, Adrenergic, alpha - drug effects; Receptors, Adrenergic, alpha - metabolism; Receptors, Dopamine - drug effects; Receptors, Dopamine - metabolism; Rotation; Structure-Activity Relationship
• ISSN: 0022-2623; 1520-4804
• DOI: 10.1021/jm00378a014

A series of tricyclic oxazines, namely, the 4-substituted 2H-naphth[1,2-b]-1,4-oxazines, have been synthesized and assayed for dopamine agonist activity. One of the members of this series, compound (+)VII-15, was found to be a remarkably potent agonist in vivo when tested in the standard 6-hydroxydopamine lesioned rat assay. The absolute configuration of the compound corresponds to that found in the active isomer of apomorphine. Its activity at the alpha 2 receptor (vs. [3H]clonidine) is relatively low. It also failed to stimulate the synthesis of cAMP in the carp retina assay, thus giving the compound a highly selective profile in favor of the D2 receptor.