Ajmalicine

Ajmalicine, also known as δ-yohimbine or raubasine, is an antihypertensive drug used in the treatment of high blood pressure.^[1] It has been marketed under numerous brand names including Card-Lamuran, Circolene, Cristanyl, Duxil, Duxor, Hydroxysarpon, Iskedyl, Isosarpan, Isquebral, Lamuran, Melanex, Raunatin, Saltucin Co, Salvalion, and Sarpan.^[1] It is an alkaloid found naturally in various plants such as Rauvolfia spp., Catharanthus roseus, and Mitragyna speciosa.^[1][2][3]

Ajmalicine

Clinical data
Routes of administration	Oral
ATC code	none
Legal status
Legal status	In general: ℞ (Prescription only)
Identifiers
IUPAC name (19α)-16,17-didehydro- 19-methyloxayohimban- 16-carboxylic acid methyl ester
CAS Number	483-04-5 Y
PubChem CID	251561
ChemSpider	390541 Y
UNII	4QJL8OX71Z
ChEBI	CHEBI:2524
ChEMBL	ChEMBL123325 Y
CompTox Dashboard (EPA)	DTXSID60904151
ECHA InfoCard	100.006.900
Chemical and physical data
Formula	C21H24N2O3
Molar mass	352.434 g·mol−1
3D model (JSmol)	Interactive image
Melting point	262.5 to 263 °C (504.5 to 505.4 °F)
SMILES O=C(OC)\C4=C\OC(C5CN3CCc1c([nH]c2ccccc12)C3CC45)C
InChI InChI=1S/C21H24N2O3/c1-12-16-10-23-8-7-14-13-5-3-4-6-18(13)22-20(14)19(23)9-15(16)17(11-26-12)21(24)25-2/h3-6,11-12,15-16,19,22H,7-10H2,1-2H3/t12-,15-,16+,19-/m0/s1 Y Key:GRTOGORTSDXSFK-XJTZBENFSA-N Y
NY (what is this?)  (verify)

Ajmalicine is structurally related to yohimbine, rauwolscine, and other yohimban derivatives.^[4] Like corynanthine, it acts as a α₁-adrenergic receptor antagonist with preferential actions over α₂-adrenergic receptors, underlying its hypotensive rather than hypertensive effects.^[1][5]

Additionally, it is a very strong inhibitor of the CYP2D6 liver enzyme, which is responsible for the breakdown of many drugs. Its binding affinity at this receptor is 3.30 nM.^[6]

Biosynthesis

Two moieties are involved in the biosynthesis of ajmalicine, the terpenoid moiety and the indole moiety.^[7] The terpenoid moiety is synthesized by the MEP pathway. The MEP pathway starts with pyruvate and D-glyceraldehyde-3-phosphate, followed by the involvement of DXS, DXR, MCT, MECS, HDS, and HDR genes. This results in isopentenyl diphosphate and dimethylallyl diphosphate which are then synthesized into secologanin. The indole moiety is brought about by the indole pathway, where tryptophan decarboxylase (TDC) catalyzes the formation of tryptamine from tryptophan. Strictosidine synthase (STR) then catalyzes the formation of strictosidine from the intermediates of the previous pathways. Strictosidine is the common precursor for all terpenoid indole alkaloids. Ajmalicine is finally synthesized under catalysis of strictosidine glucosidase (SGD).

Biosynthetic pathway of ajmalicine. Reconstruction of figure 1 in Chang, K. (2014).^[7]

See also

• Corynanthine
• Rauwolscine
• Spegatrine
• Yohimbine

References

1. Wink M, Roberts MW (1998). "Compartmentation of alkaloid synthesis, transport. and storage". Alkaloids: biochemistry, ecology, and medicinal applications. New York: Plenum Press. ISBN 0-306-45465-3.
2. Kurz WG, Chatson KB, Constabel F, Kutney JP, Choi LS, Kolodziejczyk P, et al. (May 1981). "Alkaloid Production in Catharanthus roseus cell cultures VIII". Planta Medica. 42 (1): 22–31. doi:10.1055/s-2007-971541. PMID 17401876. S2CID 28177495.
3. León F, Habib E, Adkins JE, Furr EB, McCurdy CR, Cutler SJ (July 2009). "Phytochemical characterization of the leaves of Mitragyna speciosa grown in U.S.A". Natural Product Communications. 4 (7): 907–910. doi:10.1177/1934578X0900400705. PMC 9255435. PMID 19731590. S2CID 37709142.
4. Roberts MF (1998-06-30). Alkaloids: Biochemistry, Ecology, and Medicinal Applications. Springer Science & Business Media. ISBN 978-0-306-45465-3.
5. Roquebert J, Demichel P (October 1984). "Inhibition of the alpha 1 and alpha 2-adrenoceptor-mediated pressor response in pithed rats by raubasine, tetrahydroalstonine and akuammigine". European Journal of Pharmacology. 106 (1): 203–205. doi:10.1016/0014-2999(84)90698-8. PMID 6099269.
6. Strobl GR, von Kruedener S, Stöckigt J, Guengerich FP, Wolff T (April 1993). "Development of a pharmacophore for inhibition of human liver cytochrome P-450 2D6: molecular modeling and inhibition studies". Journal of Medicinal Chemistry. 36 (9): 1136–1145. doi:10.1021/jm00061a004. PMID 8487254.
7. Chang K, Chen M, Zeng L, Lan X, Wang Q, Liao Z (2014). "Abscisic Acid Enhanced Ajmalicine Biosynthesis in Hairy Roots of Rauvolfia verticillata by Upregulating Expression of the MEP Pathway Genes". Russian Journal of Plant Physiology. 61 (1): 136–141. doi:10.1134/S102144371401004X. ISSN 1021-4437. S2CID 255013940.