(E)-Methyl 2-[(2S,3S,12bR)-3-ethyl-8-meth­oxy-1,2,3,4,6,7,12,12b-octa­hydro­indolo[2,3-a]quinolizin-2-yl]-3-methoxy­acrylate ethanol solvate

Paulo Carvalho; Edward B Furr III; Christopher McCurdy

doi:10.1107/S1600536809017309

. 2009 May 29;65(Pt 6):o1441–o1442. doi: 10.1107/S1600536809017309

(E)-Methyl 2-[(2S,3S,12bR)-3-ethyl-8-methoxy-1,2,3,4,6,7,12,12b-octahydroindolo[2,3-a]quinolizin-2-yl]-3-methoxyacrylate ethanol solvate

Paulo Carvalho ^a, Edward B Furr III ^a, Christopher McCurdy ^b,^*

PMCID: PMC2969786 PMID: 21583280

Abstract

In the title compound, C₂₃H₃₀N₂O₄·C₂H₆O, the indole derivative has four fused rings, forming an indolo[2-3a]quinolizine system, in which one six-membered ring is directly connected to the indole unit and has a distorted chair conformation. The fourth ring is also a six-membered ring, depicting a regular chair conformation. In the crystal, the molecules are linked by N—H⋯O and O—H⋯N interactions, forming a C(7) chain.

Related literature

For previous crystallographic analysis of mitragynine salts (hydrobromide and hydroiodide), see: Zacharias et al. (1965 ▶). For the method of extraction, see: Ponglux et al. (1994 ▶). For synthetic studies, see: Ma et al. (2009 ▶). For medicinal properties, see: Boyer et al. (2008 ▶); Weibrecht et al. (2008 ▶). For hydrogen-bond motifs, see: Bernstein et al. (1995 ▶).

Experimental

Crystal data

C₂₃H₃₀N₂O₄·C₂H₆O
M _r = 444.56
Orthorhombic,
a = 7.60450 (10) Å
b = 11.7534 (2) Å
c = 26.5735 (4) Å
V = 2375.11 (6) Å³
Z = 4
Cu Kα radiation
μ = 0.70 mm⁻¹
T = 100 K
0.12 × 0.09 × 0.06 mm

Data collection

Bruker APEXII CCD diffractometer
Absorption correction: none
34365 measured reflections
4158 independent reflections
3649 reflections with I > 2σ(I)
R _int = 0.083

Refinement

R[F ² > 2σ(F ²)] = 0.036
wR(F ²) = 0.089
S = 1.05
4158 reflections
295 parameters
H-atom parameters constrained
Δρ_max = 0.19 e Å⁻³
Δρ_min = −0.18 e Å⁻³
Absolute structure: Flack (1983 ▶), 1758 Friedel pairs
Flack parameter: 0.2 (2)

Data collection: APEX2 (Bruker, 2005 ▶); cell refinement: SAINT (Bruker, 2005 ▶); data reduction: SAINT; program(s) used to solve structure: SHELXS97 (Sheldrick, 2008 ▶); program(s) used to refine structure: SHELXL97 (Sheldrick, 2008 ▶); molecular graphics: SHELXTL (Sheldrick, 2008 ▶); software used to prepare material for publication: SHELXTL and ORTEP-3 (Farrugia, 1997 ▶).

Supplementary Material

Crystal structure: contains datablocks I, global. DOI: 10.1107/S1600536809017309/bx2206sup1.cif

e-65-o1441-sup1.cif^{(21.7KB, cif)}

Structure factors: contains datablocks I. DOI: 10.1107/S1600536809017309/bx2206Isup2.hkl

e-65-o1441-Isup2.hkl^{(203.8KB, hkl)}

Additional supplementary materials: crystallographic information; 3D view; checkCIF report

Table 1. Hydrogen-bond geometry (Å, °).

D—H⋯A	D—H	H⋯A	D⋯A	D—H⋯A
O5—H5⋯N2	0.82	2.07	2.876 (2)	169
N1—H1⋯O5ⁱ	0.86	2.01	2.866 (2)	170

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Symmetry code: (i) Inline graphic .

Acknowledgments

This work was supported by the NIH–NCRR (grant No. 5P20RR021919). The authors also thank the Center for Disease Control and Prevention, USA, for providing financial assistance (CDC cooperative agreements 1UO1 CI000211-03 and 1UO1 CI000362-01). This investigation was conducted in a facility constructed with support from Research Facilities Improvement Program grant No. C06Rr-14503-01 from the National Center for Research Resources, National Institutes of Health.

supplementary crystallographic information

Comment

Kratom (Mitragynia speciosa korth) is a medicinal herb endogenous to southeast Asia traditionally used as a treatment for opium withdrawal. Patients with chronic pain are increasingly aware of kratom as opioid replacement therapy. Mitragynine, the predominant alkaloid of kratom, binds with high affinity at human adrenergic, serotinergic, and adenosine CNS receptors. The binding affinity of mitragynine at mu (KD = 204 plus or minus 26 nM), delta (KD = 2250 plus or minus 47nM) and kappa (KD = 455 plus or minus 47 nM) receptors suggest that the mu-opioid agonism of mitragynine may minimize opioid withdrawal symptoms; as a kappa agonist, the molecule may oppose mu-opioid effects to modulatere inforcement and produce aversion. Furthermore, adrenergic agonist activity at alpha-2 receptors may permit kratom to mimic adjunctive therapies for opioid withdrawal such as clonidine (Weibrecht et al., 2008). The title compound has four fused rings, forming an indolo[2-3a]quinolizine system, in which one six-membered ring is directly connected to the indol moiety and has a distorted chair conformation. The fourth ring is also a six-membered ring, depicting a regular chair conformation. The molecules are linked by N—H···O and O—H···N interactions, forming a chain C(7) (Bernstein et al., 1995) along [100] directions (Fig. 2).

Experimental

Mitragynine was extracted from dried M. speciosa leaves according to the procedure published by Ponglux et al., (1994), and crystallized from a solution in ethanol.