Structural Determinants of Opioid Activity in the Orvinols and Related Structures:  Ethers of Orvinol and Isoorvinol

Abstract

A series of ethers of orvinol and isoorvinol has been prepared and evaluated in opioid receptor binding and in vitro functional assays. The most striking finding was the very large difference in kappa-opioid receptor activity between the diastereomeric ethyl ethers: 46-fold in binding, 150-fold in GPI, and 900-fold in the [(35)S]GTPgammaS assay in favor of the (R)-diastereomer. Additionally in the (R)-series there was a 700-fold increase in kappa-agonist potency in the [(35)S]GTPgammaS assay when OEt was replaced by OBn. The data can be explained in a triple binding site model: an H-bonding site, a lipophilic site, and an inhibitory site with which the 20-Me group in the (S)-ethers may interact. It appears that kappa-agonist binding of the orvinols avoids the inhibitory site in the intramolecular H-bonded conformation.

Synthesis and evaluation of κ-opioid receptor agonistic activity and antinociceptive effect of novel morphine analogues, 7α-phenyl-6α,14α-endo-etheno-tetrahydrothebaine with substituted o-, m- and p-amino group

“…1). Though it is still unknown how j agonists interact with their receptors, a model of j agonist binding was proposed based on the observed structural activity relationships (SARs), among which an H-bonding site complementary to 20b-OH was suggested to be crucial for j-opioid activities (Coop et al, 2000). Similar results were also found in our previous QSAR investigations (Li et al, 2006).…”

5-Butylthevinone: stereochemistry of the Diels–Alder reaction of 5-butylthebaine with 3-buten-2-one

“…The orvinols are an important class of opioids which are of continued interest due to their high potency as analgesics (Casy & Par®tt, 1986;Maat et al, 1999;Coop et al, 2000;Derrick et al, 2000;Meada & Coop, 2001). The preparation of the orvinols involves a Diels±Alder addition of a dienophile to the diene system of thebaine, (1), which occurs from the least hindered -face (endo-adducts).…”

Thebaine Adducts with Maleimides. Synthesis and Transformations

“…For instance, the opioid analgesic buprenorphine possesses a pharmacological profile interesting for development of antinarcotics [2]. A series of studies treats the influence of a lipophilic substituent at the C 20 atom of the buprenorphine on the pharmacological activity [3][4][5][6]. We previously reported on thebaine cycloaddition to cyclic dienophiles providing 7α,8α-fused derivatives of 6,14-endo-ethenotetrahydrothebaine [7][8][9][10].…”

“…Yields, melting points, data of mass, IR, and 1 H NMR spectra of N'-substituted 7α,8α-succinimido-6α,14α-endo-etheno-6,7,8,14-tetrahydrothebaines III, XIV, XVI-XVIII, 7α,8α-pyrrolidino-6α,14α-endo-etheno-6,7,8,14-tetrahydrothebaines XX-XXII, corresponding oripavines XXV, XXVII, XXIX, and 6-demethyltetrahydrothebaines XXVIII, XXX a OC 3 ),3.94 d.d (1H, CH, J 7.0 and 5.6), 3.99 d (1H, H 9α , J 6.4), 4.23 d (1H, H 8 , J 8.3), 4.67 d (1H, H 5β , J 1.4), 5.38 d (1H, H 19 , J 8.7), 5.75 d.d (1H, H 18 , J 8.7 and 1.4), 6.54 d (1H, H 1 , J 8.2), 6.62 d (1H, H 2 , J 8.2) 2H, CH 2 ), 1.85 m (1H, H 15 ), 1.90 m (2H, CH 2 and 1H, H 15 ), 2.47 s (3H, CH 3 N), 2.45 m (2H, H 10,16 ), 2.57 d.d.d (1H, H 16 , J gem 12.4, J vic 12.Ph) THEBAINE ADDUCTS WITH MALEIMIDES. SYNTHESIS AND TRANSFORMATIONS Table 1.…”