Synthesis and Opioid Activity of 7-Oxygenated 2,3,4,4a,5,6,7,7a-octahydro-1H-benzofuro[3,2-e]isoquinolinols

3-(Cyclopropylmethyl)-9-hydroxy-7-oxo-2,3,4,4aα,5,6,7,7aα-octahydro-1H-benzofuro[3,2-e]isoquinoline (4b) containing the ACNO ring system of morphine and a 7-keto function on ring C has been synthesized and found to possess potent PQW (ED 50 =0.15 mg/kg sc) and anti-Straub tail (ED 50 =0.02 mg/kg sc) activity. As compared to its 7-deoxy analog 1b, introduction of the 7-keto group did not significantly affect binding to any of the three opioid receptors (μ, κ, and δ), but caused a 34-fold reduction in σ-binding, suggesting reduced propensity to induce psychotomimetic effects. The C/D cis isomer of 4b (4c) was much less potent at the three opioid receptors, while displaying a slight increase in σ affinity. Both 7-hydroxy derivatives 4e and 4f were active in anti-Straub tail assay, but only the α-isomer 4e demonstrated analgesic activity in the dose range tested. In guinea pig ileum preparations, 4e was characterized as a selective full agonist at the κ opiod receptor; while its β-isomer 4f was a partial agonist, with antagonist activity observed at both μ- and κ-opiod receptors