Synthesis and κ-opioid receptor activity of furan-substituted salvinorin A analogues

Abstract

The neoclerodane diterpene salvinorin A, found in the leaves of Salvia divinorum, is a potent κ-opioid receptor agonist, making it an attractive scaffold for development into a treatment for substance abuse. Although several successful semisynthetic studies have been performed to elucidate structure-activity relationships, the lack of analogues with substitutions to the furan ring of salvinorin A has prevented a thorough understanding of its role in binding to the κ-opioid receptor. Herein we report the synthesis of several salvinorin A derivatives with modified furan rings. Evaluation of these compounds in a functional assay indicated that sterically less demanding substitutions are preferred, suggesting the furan ring is bound in a congested portion of the binding pocket. The most potent of the analogues successfully reduced drug-seeking behavior in an animal model of drug-relapse without producing the sedation observed with other κ-opioid agonists.

Figure 1

Salvinorin A is a structurally unique hallucinogen and KOR ligand. While salvinorin A, LSD, and psilocin are all hallucinogens, the latter two act through serotonin 5-HT_2A receptors. In contrast, salvinorin A is a potent and selective KOR agonist but is structurally dissimilar to other KOR ligands, such as U69,593 and nor-BNI. The closely related salvinorin A analogue herkinorin is a potent MOR agonist.

Scheme 1. Bromination and Suzuki–Miyaura Reaction of 1

Reagents and conditions: (a) NBS (1.4 equiv), Br₂ (cat.), CH₂Cl₂; (b) RB(OH)₂ (2.0 equiv), Pd₂dba₃ (0.04 equiv), SPhos (0.16 equiv), K₃PO₄ (3.0 equiv), PhMe, 60 °C. 13% of 1 was recovered from the reaction mixture. Alternate reaction conditions used: RBF₃K (1.1 equiv), Pd(dppf)·CH₂Cl₂ (0.09 equiv), Cs₂CO₃ (3.0 equiv) THF/H₂O (20:1), 65 °C.

Scheme 2. Synthesis of Alkynyl-Substituted Analogues via Sonogashira Couplings

Reagents and conditions: (a) appropriate terminal alkyne (2.0 equiv), PdCl₂(PPh₃)₂, (0.05 equiv), CuI (0.1 equiv), THF/Et₃N (1:1), 80 °C; (b) TBAF (2.0 equiv), CH₂Cl₂.

Scheme 3. Selective Reduction of 29, 10, 11, and 12

Reagents and conditions: (a) H₂, Pd/C (10%), MeOH/THF (3:2).

Scheme 4. Synthesis of Disubstituted Probes

Reagents and conditions: (a) NBS (1.0 equiv), Br₂ (1.0 equiv), CH₂Cl₂; (b) MeB(OH)₂ (4.0 equiv), Pd₂dba₃ (0.04 equiv), SPhos (0.16 equiv), K₃PO₄ (3.0 equiv), PhMe, 60 °C.

Scheme 5. Trifluoromethylation of 1 Using Photoredox Catalysis and Relevant NMR Correlations

Reagents and conditions: (a) Ru(phen)₃Cl₂·H₂O (0.02 equiv), CF₃SO₂Cl₂ (4.0 equiv), KH₂PO₄ (3.0 equiv), hν, MeCN.

Scheme 6. Synthesis of Hydroxymethyl-, Formyl-, and Cyano-Substituted Analogues

Reagents and conditions: (a) (CH₂O)_n (5.43 equiv), AcOH, 75 °C; (b) DMSO (27 equiv), (COCl)₂ (14 equiv), Et₃N (5.2 equiv), CH₂Cl₂, −78 °C to rt; (c) NH₂OH·HCl, pyr (9.3 equiv), MeOH, 65 °C; (d) TsCl (1.1 equiv), DIPEA (2.6 equiv), CH₂Cl₂.

Figure 2

Active lever responses for cocaine self-administration during baseline and extinction (pretest) and during reinstatement following a priming injection of cocaine (20 mg/kg) for 2 (A), 24 (B), and 36 (C). Repeated measures ANOVA followed by Dunnett’s multiple comparison test (*P < 0.05; **P < 0.01) (n = 5 or 6). Effect of 2 (D) (P = 0.9326), 24 (E) (P = 0.7289), and 36 (F) (P = 0.3659) on spontaneous locomotor activity in the rat shown as total ambulatory counts over 60 min. Student t test (n = 6 or 7).