SYNTHESIS AND OPIOID ACTIVITY OF 7-OXYGENATED 2,3,4,4A,5,6,7,7A-OCTAHYDRO-1H-BENZOFURO[3,2-E]ISOQUINOLIN-9-OLS

3-(Cyclopropylmethyl)-9-hydroxy-7-oxo-2,3,4,4a alpha,5,6,7,7a alpha-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 (mu, kappa, and delta), but caused a 34-fold reduction in sigma-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 o affinity. Both 7-hydroxy derivatives 4e and 4f were active in anti-Straub tail assay (ED(50) less than or equal to 0.8 mg/kg sc), but only the alpha-isomer 4e demonstrated analgesic activity (PQW ED(50) = 0.37 mg/kg sc) in the dose range tested. In guinea pig ileum preparations, 4e was characterized as a selective full agonist at the K opioid receptor (IC50 = 2.8 nM); while its beta-isomer 4f was a partial agonist (78% at 1 mu M), with antagonist activity observed at both mu- and kappa-opioid receptors.