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 (ED50 = 0.15 mg/kg sc) and anti-Straub tail (ED50 = 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 sigma affinity. Both 7-hydroxy derivatives 4e and 4f were active in anti-Straub tail assay (ED50 < or = 0.8 mg/kg sc), but only the alpha-isomer 4e demonstrated analgesic activity (PQW ED50 = 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 kappa opioid receptor (IC50 = 2.8 nM); while its beta-isomer 4f was a partial agonist (78% at 1 microM), with antagonist activity observed at both mu- and kappa-opioid receptors.
Cheng
C Y
CY
School of Pharmacy and Pharmacological Institute, College of Medicine, National Taiwan University, Taipei.
Hsin
L W
LW
Tsai
M C
MC
Schmidt
W K
WK
Smith
C
C
Tam
S W
SW
D000700:Analgesics / Q000138:chemical synthesis / Q000494:pharmacology; D000818:Animals; D001572:Benzofurans / Q000138:chemical synthesis* / Q000378:metabolism / Q000494:pharmacology*; D001665:Binding Sites; D006168:Guinea Pigs; D066298:In Vitro Techniques; D007546:Isoquinolines / Q000138:chemical synthesis* / Q000378:metabolism / Q000494:pharmacology*; D007700:Kinetics; D008297:Male; D051379:Mice; D008815:Mice, Inbred Strains; D009022:Morphine Derivatives / Q000138:chemical synthesis* / Q000378:metabolism / Q000494:pharmacology*; D009294:Narcotics / Q000138:chemical synthesis* / Q000378:metabolism / Q000494:pharmacology*; D010084:Oxidation-Reduction; D011957:Receptors, Opioid / Q000187:drug effects / Q000378:metabolism; D013329:Structure-Activity Relationship
D000700:Analgesics; D001572:Benzofurans; D007546:Isoquinolines; D009022:Morphine Derivatives; D009294:Narcotics; D011957:Receptors, Opioid