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

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-phenylsubstituted ligand is an extremely potent, high-affinity, full D 1 dopamine receptor-selective agonist.

Investigation of D1 Receptor–Agonist Interactions and D1/D2 Agonist Selectivity Using a Combination of Pharmacophore and Receptor Homology Modeling

“…studied dinapsoline analogues and discovered that the 4‐OH‐ and 6‐Et‐dinapsoline analogues (Figure 6) showed a similar affinity as dinapsoline, but the 6‐Et analogue had enhanced intrinsic activity. Bonner et al 55. recently published a novel series of octahydrobenzo[ h ]isoquinolines, of which the most potent compound ( 4 , Figure 6) shows higher affinity and similar efficacy for the D 1 receptor than do DHX and doxantrine.…”

Mapping the Catechol Binding Site in Dopamine D1Receptors: Synthesis and Evaluation of Two Parallel Series of Bicyclic Dopamine Analogues

“…We have recently synthesized and evaluated such a benz[ h ]isoquinoline compound [46] and discovered that, compared to 3d , it possesses a nearly 4-fold increase in D1-like affinity, a D1-like selectivity increase from 33-fold to 73-fold, and a nearly 3-fold increase in potency. The significant increases of affinity, selectivity, and potency over 3d are consistent with the hypothesis of an intramolecular hydrogen bond.…”

Identification of a 2-phenyl-substituted octahydrobenzo[f]quinoline as a dopamine D3 receptor-selective full agonist ligand

“…DHX and compound 4 were synthesized by our laboratory previously. 7,11 Striatal tissue used for competition binding experiments was dissected from porcine brain tissue obtained from Purdue Butcher Block and prepared as described previously. 8 …”

“…Interestingly, compound 4 , a benzo[ h ]isoquinoline with a pendant phenyl ring attached at the 5-position (two atoms displaced from the β-position), also demonstrated full agonist activity at the D 1 receptor and selectivity over the D 2 -like receptor, and has the highest functional potency of any dopamine D 1 agonist reported to date. 11 These results raised our interest in probing the approximate location of the accessory binding region in the D 1 receptor that accommodates the pendant phenyl ring. To explore further the D 1 accessory binding region, and assess the effect of position of the extended pendant accessory ring on receptor selectivity, we decided to transpose the appended phenyl ring of 4 to a location more distal from the catechol moiety, and prepared compound 5a , along with several substituted congeners.…”