trans-2,3-Dihydroxy-6a,7,8,12b-tetrahydro-6H-chromeno[3,4-c]isoquinoline:  Synthesis, Resolution, and Preliminary Pharmacological Characterization of a New Dopamine D₁Receptor Full Agonist

Abstract

We report the synthesis of trans-2,3-dihydroxy-6a,7,8,12b-tetrahydro-6H-chromeno[3,4-c]isoquinoline hydrochloride 6 and the resolution of its enantiomers. This new compound is an oxygen bioisostere of the potent dopamine D1-selective full agonist dihydrexidine. The initial synthetic approach involved, as a key step, a Suzuki coupling between a chromene triflate and a boronate ester, followed by isoquinoline formation and reduction of the resulting isoquinoline. Subsequently, a more efficient route was developed that involved conjugate addition of an aryl Grignard reagent to a 2-nitrochromene. The title compound possessed high affinity (Ki=20-30 nM) for porcine D1-like receptors in native striatal tissue and full intrinsic activity at cloned human dopamine D1 receptors but had much lower affinity at dopamine D2-like receptors (Ki=3000 nM). The binding and functional properties of this compound illustrate again the utility of constructing dopamine D1 agonist ligands around the beta-phenyldopamine pharmacophore template.

Comparison of the D1 dopamine full agonists, dihydrexidine and doxanthrine, in the 6-OHDA rat model of Parkinson's disease

“…1. Compared to DHX, DOX showed greater than 100-fold selectivity for D 1 -like over D 2 -like receptors in porcine striatal tissue and similar potency in stimulating cAMP accumulation in recombinant human D 1 dopamine receptor-expressing HEK cells (Cueva et al 2006). Initial in vivo characterization of the enantiomers of DOX showed that the (+) isomer increased locomotor activity in mice (Przybyla et al 2009), but to date there still has been no in vivo evidence for potential utility of DOX in PD.…”

“…Recently, we reported the discovery of doxanthrine (DOX), a highly D 1 receptor-selective full agonist (Cueva et al 2006). Doxanthrine was designed as a potential bioisostere of dihydrexidine, where an oxygen atom replaces a methylene unit, as illustrated in Fig.…”

C-ring expanded analogs of doxanthrine: conformation plays a critical role

“…22 The synthetic approach we used to construct the doxanthrine ring system allowed facile access to various β-substituents, and we envisioned that an increase in β-substituent volume and flexibility could serve to probe the directionality and/or steric constraints of the β-phenyl accessory binding region. In this report we describe efforts that led to novel molecules 5 and 6, which, although they ultimately proved inactive, supported our hypothesis that the accessory phenyl ring must be positioned in a relatively constrained area.…”

“…22 The synthesis of 5 is based on a key diastereoselective conjugate addition of heteroatom-promoted laterally lithiated o-tolyloxazoline 7 to nitroalkene 8. Nitrochromene 8 was prepared as reported previously 22 by a one-step procedure involving conjugate addition of sesam aldehyde to nitroethene, generated in situ. In the course of this work we discovered that O-acetylation of sesamol prior to formylation provided the required phenolic sesam aldehyde pure, and in good yield.…”

Therapeutic and Diagnostic Agents for Parkinson's Disease

“…However, A-77636 showed rapid desensitization to its beneficial effects [211], possibly related to its prolonged action (>20 h; [200]). Other conformationally restricted analogs containing the b-phenyldopamine pharmacophore continue to be reported, including, some with impressive D 1 -type over D 2 -type receptor agonist activity [212], however, in vivo studies with D 1 -agonists have given disappointing results.…”