[Show abstract][Hide abstract] ABSTRACT: A novel class of isochroman dopamine analogues, originally reported by Abbott Laboratories, have >100-fold selectivity for D₁-like over D₂-like receptors. We synthesized a parallel series of chroman compounds and showed that repositioning the oxygen atom in the heterocyclic ring decreases potency and confers D₂-like receptor selectivity to these compounds. In silico modeling supports the hypothesis that the altered pharmacology for the chroman series is due to potential intramolecular hydrogen bonding between the oxygen in the chroman ring and the meta-hydroxy group of the catechol moiety. This interaction realigns the catechol hydroxy groups and disrupts key interactions between these ligands and critical serine residues in TM5 of the D₁-like receptors. This hypothesis was tested by the synthesis and pharmacological evaluation of a parallel series of carbocyclic compounds. Our results suggest that if the potential for intramolecular hydrogen bonding is removed, D₁-like receptor potency and selectivity are restored.
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[Show abstract][Hide abstract] ABSTRACT: By combining the structural features of dinoxyline and Abbott isochromans into a single, conformationally-constrained compound, we anticipated the development of a new ligand with high affinity, selectivity, and full efficacy at the dopamine D1 receptor isoform. Synthetic difficulties prevented the completion of the initial desired target molecule 1 due to the instability of the benzylic oxygen functionality. When the benzyl group was replaced (or removed altogether) with various alkyl groups, however, the resulting compounds were stable. Instead of a D1 selective ligand, we obtained two compounds that are selective dopamine D2 agonists with potency comparable to the prototypical D2 agonist quinpirole (56 EC50 = 19 nM, 65 EC50 = 11nM. A trend was observed, both at D1 and D2 receptors, where increasing the size of the substituent at the 2-position led to decreased potency.