Modification of the furan ring of salvinorin A: identification of a selective partial agonist at the kappa opioid receptor

Abstract

In an effort to find novel agents which selectively target the kappa opioid receptor (KOPR), we modified the furan ring of the highly potent and selective KOPR agonist salvinorin A. Introduction of small substituents at C-16 was well tolerated. 12-epi-Salvinorin A, synthesized in four steps from salvinorin A, was a selective partial agonist at the KOPR. No clear SAR patterns were observed for C-13 aryl ketones. Introducing a hydroxymethylene group between C-12 and the furan ring was tolerated. Small C-13 esters and ethers gave weak KOPR agonists, while all C-13 amides were inactive. Finally, substitution of oxadiazoles for the furan ring abolished affinity for the KOPR. None of the compounds displayed any KOPR antagonism or any affinity for mu or delta opioid receptors.

Figure 1

(stereoview). Crystal structure of 12-epi-salvinorin A (6) showing 50% probability displacement ellipsoids. Hydrogen atoms are shown as spheres of arbitrary radius.

Figure 2

12-epi-Salvinorin A (6) exhibits partial agonist properties in the [³⁵S]GTPγS assay. At 10 μM, compound 6 significantly reduced [³⁵S]GTPγS binding induced by U50,488 ranging from 3 × 10⁻⁸ to 10⁻⁵ M (Student’s t test, *, P < 0.01).

Figure 3

(stereoview). Superimposition of the crystal structures of 1 (dark grey) and 6 (light grey).

Scheme 1

Syntheses of 16-substituted salvinorin derivatives. Reagents and conditions: (a) NBS, CHCl₃, r.t., 10–62%; (b) tributylvinyltin, Pd(PPh₃)₄, toluene, 80°C, 58%.

Scheme 2

Synthesis of 12-epi-salvinorin A. Reagents and conditions: (a) 5% aqueous KOH, 80°C, 95%; (b) Ac₂O, pyridine, r.t., 48%; (c) AcOH, 118°C; (d) TMSCHN₂, CH₃CN, r.t., 19%, over two steps.

Scheme 3

Syntheses of C-13 alcohol and ethers. Reagents and conditions: (a) NaIO₄, RuCl₃.3H₂O, CH₂Cl₂/CH₃CN/H₂O, 63%; (b) BH₃.THF, THF, 55°C, 46%; (c) RI, Ag₂O, CH₃CN, 60°C, 12–15%; (d) Ac₂O, Et₃N, CH₂Cl₂, r.t., 79%.

Scheme 4

Syntheses of C-13 arylketones and alcohol. Reagents and conditions: (a) (COCl)₂, CH₂Cl₂, r.t.; (b) RSn(nBu)₃, Pd(PPh₃)₄toluene, 80–100°C, 7–57%, over two steps; (c) NaBH₄, CH₃OH, 0°C, 19%.

Scheme 5

Syntheses of C-13 esters and amides. Reagents and conditions: (a) TMSCHN₂, CH₃OH, toluene, r.t., 48%; (b) ROH, EDCI, DMAP, CH₂Cl₂, r.t., 26–54%; (c) RNH₂, EDCI, HOBt, CH₂Cl₂, r.t., 45–72%.

Scheme 6

Syntheses of C-13 oxadiazoles. Reagents and conditions: (a) RC(=NOH)NH₂, EDCI, HOBt, CH₂Cl₂, r.t.; (b) toluene, 110°C, 10–45%, over two steps.