Electrophilic opioid ligands. Oxygen-tethered .alpha.-methylene-.gamma.-lactone, acrylate, isothiocyanate, and epoxide derivatives of 6.beta.-naltrexol

Abstract

O6-Ether derivatives of 6 beta-naltrexol in which the ether substituent includes various electrophilic groups have been synthesized in an effort to examine structure-activity requirements at the 6 beta-substituent for receptor affinity and irreversibility of binding in opioid receptor preparations. A series of tethered 6 beta-ethers having terminal epoxides, alpha-methylene-gamma-lactones, and an isothiocyanate group were prepared. The stereochemistry of the alpha-methylene-gamma-lactones was established by convergent synthesis of their reduction products from epoxides of known absolute stereochemistry. In general, the tested compounds showed comparable affinity and selectivity for the receptor subtypes. All were found with high affinity for mu-sites. The terminal epoxide ether diastereomers 8 and 9 were not bound irreversibly in the assay for total opioid receptors. The alpha-methylene-gamma-lactone diastereomers 10 and 11, and their O14-acetyl precursors 20 and 21, respectively, varied in their irreversible effects, but where noted these effects were mu-site selective. Methacrylate ether 7 and isothiocyanate ether 12 were bound irreversibly at both mu- and delta-sites.

Isothiocyanate-Substituted Benzyl Ether Opioid Receptor Ligands Derived from 6.beta.-Naltrexol

“…After conditioning the silica gel with CH2Cl2 (100 mL), the residue was eluted sequentially with CH2CI2 (150 mL), 80:20 CH2Cl2:EtOAc (300 mL), and 50:50 CH2Cl2:EtOAc (200 mL). The product was eluted with the second eluent mixture, and removed of solvent by rotary evaporation afforded 20 as a yellow foam (390 mg, 63% yield): NMR (CDCls) ó 8.03 (d, J = 8.2 Hz, 1 H, C-24 H), 7.98 (d, J = 8.2 Hz, 1 H, C-27 H), 7.52 (dd, J = 7.6, 7.6 Hz, 1 H, C-26 H), 7.39-7.47 (m, 6 H, C-23' 3 H, C-27' 3 H), 7.33 (dd, J = 7.8, 7.8 Hz, 1 H, C-25 ), 7.12-7.26 (m, 9 H, C-24' 3 H, C-25' 3 H, C-26' 3 H), 6.47 (d, J = 8.2 Hz, 1 H, C-2 H), 6.22 (d, J = 8.3 Hz, 1 H, C-l ), 5.09 (d, J = 15.5 Hz, 1 H, C-21 H), 5.01 (d, J = 15.2 Hz, 1 H, C-21 H), 4.45 (d, J = 6.4 Hz, 1 H, C-5/3 ), 3.10-3.22 (m, 1 H, C-6a H), 2.99 (d, J = 4.9 Hz, 1 H, C-9 H), 2.86 (d, J = 18.6 Hz, 1 H, C-10/3 H), 2.37-2.55 (m, 2 H, C-lOa H, C-16 H), 2.29 (d, J = 6.5 Hz, 2 H, C-17 2 ), 1.72-2.12 (m, 4 H, C-7 2 H, C-15 H, C-16 ), 1.48-1.59 (m, 1 H, C-8 ), 1.14-1.28 (m, 1 H, C-8 ), 1.02-1.11 (m, 1 H, C-15 ), 0.72-0.87 (m, 1 H, C-18 ), 0.44-0.54 (m, 2 H, C-19 H, C-20 ), 0.04-0.12 (m, 2 H, C-19 H', C-20 H'). organic fractions were washed with H20 (15 mL), and removal of solvent by evaporation yielded a viscous burgundy oil which was purified by flash column chromatography.…”

“…Structural modification of naltrexone has shown that C-6 substitution, even with relatively large substituents, affords potent agents. Some examples include 6-desoxy-6-methylenenaltrexone (nalmefene (2) and 6/3-methyl-6a-naltrexol (3), which are potent opioid antagonist,1 and compounds with even larger substituents attached at the C-6 position, such as /3-chlomaltrexamine (/3-CNA) (4) and /3-funaltrexamine (/3-FNA) (5), which are important electrophilic ligands. 2 The C-6 position has served as the location for a variety of substituents which have led to several derivatives of the 6/3-and 6a-amines, including amides as conjugate addition acceptors, thiol reagents, and -haloacetamides.…”

“…2 The C-6 position has served as the location for a variety of substituents which have led to several derivatives of the 6/3-and 6a-amines, including amides as conjugate addition acceptors, thiol reagents, and -haloacetamides. 3 In addition, several oxygen-containing compounds have also been prepared, including spiro -methylene-y-lactones and related 6-tethered ethers which have shown high affinity for µ-and d-opioid receptors.4 4,5 OH N jf H On the basis of the activity of several agents in these series, we have explored a series of 6/3-O-benzyl ethers ® Abstract published in Advance ACS Abstracts, January 15, 1995. in which the isothiocyanate functionality is incorporated to serve as a probe for potential nucleophilic sites at opioid receptors. The isothiocyanate fucntionality has been widely used in the opioid receptor field.6 Ligands were chosen in which the isothiocyanate is located at the ortho, meta, and para positions of the added benzyl group, both attached directly to the aromatic ring (6)(7)(8) and attached one carbon away from it, as aliphatic isothiocyanates 9-11.…”