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. 2010 Sep 15;18(18):6763-70.
doi: 10.1016/j.bmc.2010.07.052. Epub 2010 Jul 27.

Facile synthesis of octahydrobenzo[h]isoquinolines: novel and highly potent D1 dopamine agonists

Lisa A Bonner  1 , Benjamin R Chemel, Val J Watts, David E Nichols
Affiliations

Facile synthesis of octahydrobenzo[h]isoquinolines: novel and highly potent D1 dopamine agonists

Lisa A Bonner et al. Bioorg Med Chem. .

Abstract

The octahydrobenzo[h]isoquinoline scaffold is of interest as a conformationally-restricted phenethylamine that may be useful for constructing biologically active products. Surprisingly, however, no tractable synthesis of this ring system has been reported. We now describe a facile method for obtaining this framework, and illustrate that our approach is easily amenable to substitutions at the 5-position. Importantly, we demonstrate that the 7,8-dihydroxy-5-phenyl-substituted ligand is an extremely potent, high-affinity, full D1 dopamine receptor-selective agonist.

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Figures

Figure 1
Figure 1
Trans-β-dopamine
Figure 2
Figure 2
Known D1-like dopamine agonists
Figure 3
Figure 3
Target compounds: octahydrobenzo[h]isoquinolines 1, 2, and 3
Scheme 1
Scheme 1
Synthesis of intermediate 7 by paraconic acid decarboxylation
Scheme 2
Scheme 2
Synthesis of target compounds 1, 2, and 3 by conjugate addition to unsaturated nitriles
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