Standard protecting groups create potent and selective κ opioids: Salvinorin B alkoxymethyl ethers
Graphical abstract
Introduction
Salvinorin A (1) is a potent and selective naturally-occurring κ (kappa) opioid.1 As one of very few reported non-nitrogenous opioids,2 salvinorin A has created new opportunities for understanding the mechanisms of ligand binding at opioid receptors, which might facilitate drug discovery. One objective has been the development of selective antagonists or partial agonists at κ opioid receptors; such agents have potential utility in the treatment of depression or mania,3 debilitating conditions for which all current treatments have significant limitations (e.g., poor efficacy, delayed onset, marked side effects). Many derivatives of 1 have now been tested at opioid receptors.4 Binding affinity and potency are almost invariably reduced; very few derivatives exhibit potency comparable to 1. Most active derivatives, like the parent compound, are full agonists, but recently partial agonists and antagonists have been reported.4, 5 This is potentially significant, since the few available selective κ antagonists exhibit extremely slow onset (∼24 h) and long duration of action (>3 weeks),6 which complicates their use in the study or treatment of psychiatric conditions such as depression.7 However, the modifications which appear to confer partial agonist and antagonist activities on salvinorin derivatives also dramatically reduce binding affinity and selectivity;4, 5 methods to optimize these parameters would therefore be useful.
To date the most thoroughly studied functional group of 1 is the C-2 acetate. Interestingly, while deacetylation (giving 2) dramatically lowers affinity and potency,8 demethyl and deoxy analogues 39 and 4b8 each show only modestly reduced affinity. This suggests that these two portions of the acetate may be involved in separate, synergistic interactions with the receptor. Only one derivative with greater potency than 1 has been reported to date: methoxymethyl (MOM) ether 5.10 The increased affinity of 5 may be due to the additional sp3-hybridized oxygen, especially considering the lower affinity of its closest sp2-hybridized analogue, 3. Alternatively, the terminal methyl group of 5 might create an additional interaction, which could be explored by the substitution of other alkoxy groups. A related question is whether methylation of the acetal carbon would further increase potency, as with formate 3. In hopes of optimizing the C-2 substituent, we explored these questions using related protecting groups.
Section snippets
Chemistry
Deacetylation11 of 1, isolated from dried Salvia divinorum leaves as previously described,12 gave 2. MOM ether 5 was prepared from 2 and CH3OCH2Cl as previously described.13 The published 1H NMR data13 required amendment. The molecular formula, not previously established, was confirmed by HRMS. The ethoxymethyl (EOM) ether 6 and several other standard alkoxymethyl ethers were prepared similarly (Scheme 1; see Table 1 for individual structures).14
For the more unusual alkoxymethyl ethers 7–12,
Results and discussion
Binding affinities and potencies at the κ receptor are shown in Table 1. All compounds were full agonists, with efficacy approximately equal to that of U50,488H. All compounds except 14 showed submicromolar affinity and potency, generally in the low nanomolar range. None of the compounds bound to μ or δ receptors (Ki > 1 μM). This series as a whole shows markedly higher affinity and selectivity than previously reported series of derivatives of 1.
Among the n-alkoxymethyl ethers 5–8, the ethyl
Conclusions
It is fortuitous that standard protecting groups, stable and unreactive under a wide range of harsh conditions, should also confer high potency. For synthetic transformations elsewhere in the salvinorin scaffold, this permits the use of conditions incompatible with an acetate or hydroxyl. The resulting derivatives may also possess higher affinity and selectivity than the corresponding acetate, which would be valuable in ameliorating the effects of transformations elsewhere in the parent
General experimental conditions
1H NMR (300 MHz) and 13C NMR (75.5 MHz) chemical shifts are referenced to residual solvent peaks as internal standards: CDCl3 (7.26 and 77 ppm), C6D6 (7.16 and 128 ppm), and C6D5N (135.5 ppm). 19F NMR chemical shifts are referenced to CCl3F (0 ppm). Where the coupling constants of a discrete multiplet could not be determined, the separation of the outermost peaks (Δν) is given in Hz. Flash column chromatography (FCC) was performed on silica gel (230–400 mesh, 60 Å), eluting with a stepped gradient
Acknowledgments
This work was supported by grants from the Stanley Medical Research Institute, the National Institute of Mental Health (MH63266), the National Alliance for Research on Schizophrenia and Depression (NARSAD), and the Engelhard Foundation.
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