Short synthesis of a novel class of salvinorin A analogs with hemiacetalic structure

Abstract

Novel semisynthetic analogs of salvinorin A, a full agonist having extraordinary affinity as well as selectivity for the κ-opioid receptor (KOR), were obtained in good yields. The derivatives are remarkable for their unusual and unique hemiacetal structure in the salvinorin series of compounds. The formation of the hemiacetal occurs with epimerization at C-12, thus preserving the original configuration of salvinorin A. The dimethyl ester derivative of the hemiacetal was found to have an affinity for both KOR and MOR (μ-opioid receptor).Keywords salvinorin A; KOR ligands; hemiacetal; dual afinity Salvinorin A, a secondary metabolite isolated from the leaves of Salvia divinorum, is a neoclerodane diterpenoid with a strong hallucinogenic activity. It has been shown to have high affinity and selectivity for KOR. 1 Salvinorin A represents an attractive lead compound for drug development due to its strong effects on human mood and low toxicity. In the last two years numerous derivatives and analogs of salvinorin A were synthesized showing a broad range of KOR affinities. 2 Synthesis of new analogs of salvinorin A is important for generating structure-receptor affinity data and for design of agents with therapeutic potential. Some of the chemical modifications of salvinorin A have produced analogs with changed pharmacological profiles from full κ-agonist to partial δ-or μ-agonists or antagonists. 2i,2m,3 Recently, modifications of the furan ring yielded the first analogs with κ-antagonistic activity. 2bIn this paper we report the synthesis of the hemiacetal (2) and its derivatives starting from salvinorin A. Refluxing 1 with 5% aqueous KOH surprisingly gave only one product according to thin-layer chromatography. 4 (Scheme 1).

Neuropharmacology of the Naturally Occurring κ-Opioid Hallucinogen Salvinorin A

“…Hydrolysis of the C-ring lactone has been reported (Fig. 7C), and hemiacetal derivatives 173 to 177 exhibit generally poor affinity for KOP receptors (Bikbulatov et al, 2008;Béguin et al, 2009;Lee et al, 2010). The diester derivative 175 displayed the highest binding affinity for KOP and MOP receptors (K i ϭ 219 Ϯ 59 nM and KϪ i ϭ 1926 Ϯ 147 nM, respectively), while acetylation (176) greatly diminished affinity.…”

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

“…The structure of 4 , featuring inverted configuration at C-12, was firmly established by X-ray crystallography 25. Interestingly, related diacids have been prepared under the same conditions from diterpenoids lacking the C-1 ketone 26.…”

“…The cloudy mixture was then extracted into EtOAc. Drying (MgSO 4 ) and concentration in vacuo gave 4 25 (650 mg, 95%) as a yellow foam. R f 0.21 (9:1, CH 2 Cl 2 /CH 3 OH); 1 H NMR (300 MHz, CD 3 OD): δ 7.47 (dt, J = 1.6, 0.8 Hz, 1H), 7.40 (t, J = 1.7 Hz, 1H), 6.44 (dd, J = 1.8, 0.7 Hz, 1H), 5.09 (dd, J = 11.8, 1.6 Hz, 1H), 3.53 (dd, J = 11.9, 5.0 Hz, 1H), 2.23 (dd, J = 13.2, 2.7 Hz, 1H), 2.15 (dd, J = 12.9, 3.0 Hz, 1H), 2.02 – 1.89 (m, 3H), 1.82 (dt, J = 13.3, 3.1 Hz, 1H), 1.74 – 1.55 (m, 3H), 1.53 (s, 3H), 1.43 – 1.30 (m, 1H), 1.34 (s, 1H), 1.23 (s, 3H); 13 C NMR (75 MHz, CD 3 OD): δ 177.3, 176.6, 144.0, 140.6, 128.9, 110.1, 98.3, 75.2, 62.6, 56.8, 55.3, 55.3, 51.2, 41.4, 37.8, 37.1, 30.4, 22.4, 18.9, 16.1.…”

“…Bikbulatov and coworkers recently reported that refluxing 1 in aqueous KOH gave diacid 4 in 69% yield 25. The structure of 4 , featuring inverted configuration at C-12, was firmly established by X-ray crystallography 25.…”

“…We prepared 4 in 95% yield using a slight modification of the published procedure (Scheme 2). 25 Standard acetylation then afforded monoacetate 5 in moderate yield. The hemiacetal cleavage conditions reported by Bikbulatov et al (catalytic AcOH or PTSA, CH 2 Cl 2 , r.t.)25 were without effect on our substrate.…”