Dopaminergic activity of substituted 6-chloro-1-phenyl-2,3,4,5-tetrahydro-1H-3-benzazepines

• Published in: Journal of medicinal chemistry 1982-04, Vol.25 (4), p.352-358
• Main Authors: Pfeiffer, Francis R., Wilson, James W., Weinstock, Joseph, Kuo, George Y., Chambers, Pamela A., Holden, Kenneth G., Hahn, Richard A., Wardell, Joseph R., Alfonso, J. Tobia
• Format: Article
• Language: English
• Subjects: Animals; Benzazepines - chemical synthesis; Benzazepines - pharmacology; Chemical Phenomena; Chemistry; Dogs; Dopamine - physiology; Hemodynamics - drug effects; Molecular Conformation; Receptors, Dopamine - drug effects; Renal Circulation - drug effects; Vasodilator Agents - chemical synthesis
• ISSN: 0022-2623; 1520-4804
• DOI: 10.1021/jm00346a005

6-Chloro-7,8-dihydroxy-1-phenyl-2,3,4,5-tetrahydro-1H-3-benzazepines were synthesized and evaluated as agonists of central and peripheral dopamine receptors. These benzazepines were prepared by cyclization of certain amino alcohols followed by demethylation of the 7,8-dimethoxy groups of the precursors to the 7,8-catecholic moiety. Preliminary evidence of dopaminergic activity was determined in anesthetized dogs by measuring the effects on renal blood flow and calculating the accompanying changes in renal vascular resistance. The most potent compounds contained an hydroxyl group on the 1-phenyl group or were substituted at the 3' position with a chloro, methyl, or trifluoromethyl group. Evidence for central dopaminergic activity was obtained by measuring rotational effects in rats lesioned in the substantia nigra and also in an in vitro assay which measured stimulation of rat striatal adenylate cyclase. The compounds with the best central dopaminergic activity were generally the benzazepines which were the most lipophilic, were substituted on the 3' position of th 1-phenyl group, and contained either a 3-N-methyl or 3-N-allyl group.