Synthesis of 4-aminomethylchromans: Novel dopamine D 2-selective agonists
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.
Degree
Ph.D.
Advisors
Nichols, Purdue University.
Subject Area
Pharmacology|Organic chemistry
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