2H-[1]Benzopyrano[3,4-b]pyridines. Synthesis and activity at central monoamine receptors

Abstract

Two general synthetic approaches to a novel series of 2H-[1]benzopyrano[3,4-b]pyridines are described together with their receptor binding profile at a variety of monoamine receptors in mammalian brain tissue. The biologically active members of this series fall into into one of two broad classes: 3,4,4a,5-tetrahydro-2H-[1]benzopyrano[3,4-b]pyridines or trans-1,3,4,4a,5,10b-hexahydro-2H-[1]benzopyrano[3,4-b]pyridines. By appropriate pharmacophoric modification potent selective ligands for D2, alpha-2, 5HT1A, and 5HT2 receptors may be obtained. The previously published in vivo data on certain key representatives of these series are also summarized.

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

“…6,7-Methylenedioxy-4-trifluoromethanesulfonyl-2 H -chromene (12). With conditions described by Pal, 11 (8.7 g, 0.045 mol) was dissolved in 300 mL of dry THF and cooled to −78 °C, and 50 mL of a sodium bis(trimethylsilyl)amide solution (1.0 M in THF, 0.050 mol) was added. The solution was stirred for 1 h at −78 °C.…”

“…16 Incorporation of other heteroatoms into the tether, such as sulfur or nitrogen, did not afford active compounds. 17 We were encouraged to expand our search for other oxygen bioisosteres by the results of Horn et al 18 and of Hutchison et al, 19 who reported that both 4 and 5 possessed significant dopaminergic activity. Their successes using heteroatom replacement in known dopaminergic ligands, and analogies to our structural series, convinced us to prepare 6, an analogue of 1 in which the ethyl tether between the catechol and tetrahydroisoquinoline substructures was replaced with an oxymethylene ether bridge.…”