Ajmaline

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Ajmaline
Ajmaline.svg
Ajmaline-from-xtal-3D-bs-17.png
Clinical data
Trade names Gilurytmal, Ritmos, Aritmina
AHFS/Drugs.com International Drug Names
ATC code
Identifiers
  • (17R,21R)-ajmalan-17,21-diol
    OR
    (1R,9R,10S,13R,14R,16S,18S)- 13-ethyl- 8-methyl- 8,15-diazahexacyclo [14.2.1.01,9.02,7.010,15.012,17] nonadeca- 2(7),3,5-triene- 14,18-diol
CAS Number
PubChem CID
DrugBank
ChemSpider
UNII
KEGG
ChEMBL
CompTox Dashboard (EPA)
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Chemical and physical data
Formula C20H26N2O2
Molar mass 326.440 g·mol−1
3D model (JSmol)
  • CC[C@H]1[C@H]5C[C@@H]4N([C@@H]1O)[C@H]6C[C@]3(c2ccccc2N(C)[C@H]34)[C@H](O)C56
  • InChI=1S/C20H26N2O2/c1-3-10-11-8-14-17-20(12-6-4-5-7-13(12)21(17)2)9-15(16(11)18(20)23)22(14)19(10)24/h4-7,10-11,14-19,23-24H,3,8-9H2,1-2H3/t10-,11+,14-,15-,16?,17-,18+,19+,20+/m0/s1 Yes check.svgY
  • Key:CJDRUOGAGYHKKD-SXKXKDIKSA-N Yes check.svgY
 X mark.svgNYes check.svgY  (what is this?)    (verify)

Ajmaline (also known by trade names Gilurytmal, Ritmos, and Aritmina) is an alkaloid that is classified as a 1-A antiarrhythmic agent. It is often used to induce arrhythmic contraction in patients suspected of having Brugada syndrome. Individuals suffering from Brugada syndrome will be more susceptible to the arrhythmogenic effects of the drug, and this can be observed on an electrocardiogram as an ST elevation.

Contents

The compound was first isolated by Salimuzzaman Siddiqui in 1931 [1] from the roots of Rauvolfia serpentina . He named it ajmaline, after Hakim Ajmal Khan, one of the most illustrious practitioners of Unani medicine in South Asia. [2] Ajmaline can be found in most species of the genus Rauvolfia as well as Catharanthus roseus . [3] In addition to Southeast Asia, Rauvolfia species have also been found in tropical regions of India, Africa, South America, and some oceanic islands. Other indole alkaloids found in Rauvolfia include reserpine, ajmalicine, serpentine, corynanthine, and yohimbine. While 86 alkaloids have been discovered throughout Rauvolfia vomitoria , ajmaline is mainly isolated from the stem bark and roots of the plant. [3]

Due to the low bioavailability of ajmaline, a semisynthetic propyl derivative called prajmaline (trade name Neo-gilurythmal) was developed that induces similar effects to its predecessor but has better bioavailability and absorption. [4]

Biosynthesis

Ajmaline is widely dispersed among 25 plant genera, but is of significant concentration in the Apocynaceae family. [5] Ajmaline is a monoterpenoid indole alkaloid, composed of an indole from tryptophan and a terpenoid from iridoid glucoside secologanin. Secologanin is introduced from the triose phosphate/pyruvate pathway. [6] Tryptophan decarboxylase (TDC) remodels tryptophan into tryptamine. Strictosidine synthase (STR), uses a Pictet–Spengler reaction to form strictosidine from tryptamine and secologanin. Strictosidine is oxidized by P450-dependent sarpagan bridge enzymes (SBE); to make polyneuridine aldehyde. Of the sarpagan-type alkaloids, polyneuridine is a key entry into the ajmalan-type alkaloids. [7] [8] Polyneuridine Aldehyde is methylated by polyneuridine aldehydeesterase (PNAE), to synthesize 16-epi-vellosimine, which is acetylated to vinorine by vinorine synthase (VS). Vinorine is oxidized by vinorine hydroxylase (VH) to make vomilenine. Vomilenine reductase (VR) conducts a reduction of vomilenine to 1,2-dihydrovomilenine, using the cofactor NADPH. 1,2-dihydrovomilenine, is reduced by 1,2-dihydrovomilenine reductase (DHVR) to 17-O-acetylnorajmaline, with the same cofactor as VR: NADPH. 17-O-acetylnorajmaline is deacetylated by acetylajmalan esterase (AAE), to form norajmaline. Finally, norajmaline methyl transferase (NAMT) methylates norajmaline resulting in our desired compound: ajmaline. [9]


Ajmaline Biosynthesis Ajaline1.jpg
Ajmaline Biosynthesis

Mechanism of action

Schematic diagram of normal sinus rhythm for a human heart as seen on an electrocardiogram. SinusRhythmLabels.png
Schematic diagram of normal sinus rhythm for a human heart as seen on an electrocardiogram.

Ajmaline [10] was first discovered to lengthen the refractory period of the heart by blocking sodium ion channels, [3] but it has also been noted that it is also able to interfere with the hERG (human Ether-a-go-go-Related Gene) potassium ion channel. [11] In both cases, Ajmaline causes the action potential to become longer and ultimately leads to bradycardia. When ajmaline reversibly blocks hERG, repolarization occurs more slowly because it is harder for potassium to get out due to less unblocked channels, therefore making the RS interval longer. Ajmaline also prolongs the QR interval since it can also act as sodium channel blocker, therefore making it take longer for the membrane to depolarize in the first case. In both cases, ajmaline causes the action potential to become longer. Slower depolarization or repolarization results in a lengthened QT interval (the refractory period), and therefore makes it take more time for the membrane potential to get below the threshold level so the action potential can be re-fired. Even if another stimulus is present, action potential cannot occur again until after complete repolarization. Ajmaline causes action potentials to be prolonged, therefore slowing down firing of the conducting myocytes which ultimately slows the beating of the heart.

Diagnosis of Brugada syndrome

(A) Normal electrocardiogram pattern in the precordial leads, (B) changes in Brugada syndrome. The arrow indicates the characteristic elevated ST segment. Brugada EKG Schema.jpg
(A) Normal electrocardiogram pattern in the precordial leads, (B) changes in Brugada syndrome. The arrow indicates the characteristic elevated ST segment.

Brugada syndrome is a genetic disease that can result in mutations in the sodium ion channel (gene SCN5A) of the myocytes in the heart. [12] Brugada syndrome can result in ventricular fibrillation and potentially death. It is a major cause of sudden unexpected cardiac death in young, otherwise healthy people. [13] While the characteristic patterns of Brugada syndrome on an electrocardiogram may be seen regularly, often the abnormal pattern is only seen spontaneously due to unknown triggers or after challenged by particular drugs. Ajmaline is used intravenously to test for Brugada syndrome since they both affect the sodium ion channel. [14] In an afflicted person who was induced with ajmaline, the electrocardiogram would show the characteristic pattern of the syndrome where the ST segment is abnormally elevated above the baseline. Due to complications that could arise with the ajmaline challenge, a specialized doctor should perform the administration in a specialized center capable of extracorporeal membrane oxygenator support. [15]

See also

Related Research Articles

<span class="mw-page-title-main">Brugada syndrome</span> Heart conduction disease

Brugada syndrome (BrS) is a genetic disorder in which the electrical activity of the heart is abnormal due to channelopathy. It increases the risk of abnormal heart rhythms and sudden cardiac death. Those affected may have episodes of syncope. The abnormal heart rhythms seen in those with Brugada syndrome often occur at rest. They may be triggered by a fever.

<span class="mw-page-title-main">Repolarization</span> Change in membrane potential

In neuroscience, repolarization refers to the change in membrane potential that returns it to a negative value just after the depolarization phase of an action potential which has changed the membrane potential to a positive value. The repolarization phase usually returns the membrane potential back to the resting membrane potential. The efflux of potassium (K+) ions results in the falling phase of an action potential. The ions pass through the selectivity filter of the K+ channel pore.

<span class="mw-page-title-main">Indole alkaloid</span> Class of alkaloids

Indole alkaloids are a class of alkaloids containing a structural moiety of indole; many indole alkaloids also include isoprene groups and are thus called terpene indole or secologanin tryptamine alkaloids. Containing more than 4100 known different compounds, it is one of the largest classes of alkaloids. Many of them possess significant physiological activity and some of them are used in medicine. The amino acid tryptophan is the biochemical precursor of indole alkaloids.

<span class="mw-page-title-main">Salimuzzaman Siddiqui</span> Pakistani organic chemist (1897–1994)

Salimuzzaman Siddiqui, was a Pakistani organic chemist specialising in natural products, and a professor of chemistry at the University of Karachi.

SCN5A Protein-coding gene in the species Homo sapiens

Sodium channel protein type 5 subunit alpha, also known as NaV1.5 is an integral membrane protein and tetrodotoxin-resistant voltage-gated sodium channel subunit. NaV1.5 is found primarily in cardiac muscle, where it mediates the fast influx of Na+-ions (INa) across the cell membrane, resulting in the fast depolarization phase of the cardiac action potential. As such, it plays a major role in impulse propagation through the heart. A vast number of cardiac diseases is associated with mutations in NaV1.5 (see paragraph genetics). SCN5A is the gene that encodes the cardiac sodium channel NaV1.5.

<span class="mw-page-title-main">Prajmaline</span> Chemical compound

Prajmaline (Neo-gilurythmal) is a class Ia antiarrhythmic agent which has been available since the 1970s. Class Ia drugs increase the time one action potential lasts in the heart. Prajmaline is a semi-synthetic propyl derivative of ajmaline, with a higher bioavailability than its predecessor. It acts to stop arrhythmias of the heart through a frequency-dependent block of cardiac sodium channels.

In enzymology, a 1,2-dihydrovomilenine reductase (EC 1.3.1.73) is an enzyme that catalyzes the chemical reaction

<span class="mw-page-title-main">Camptothecin</span> Chemical compound

Camptothecin (CPT) is a topoisomerase inhibitor. It was discovered in 1966 by M. E. Wall and M. C. Wani in systematic screening of natural products for anticancer drugs. It was isolated from the bark and stem of Camptotheca acuminata, a tree native to China used in traditional Chinese medicine. It has been used clinically in China for the treatment of gastrointestinal tumors. CPT showed anticancer activity in preliminary clinical trials, especially against breast, ovarian, colon, lung, and stomach cancers. However, it has low solubility and adverse effects have been reported when used therapeutically, so synthetic and medicinal chemists have developed numerous syntheses of camptothecin and various derivatives to increase the benefits of the chemical, with good results. Four CPT analogues have been approved and are used in cancer chemotherapy today: topotecan, irinotecan, belotecan, and trastuzumab deruxtecan. Camptothecin has also been found in other plants including Chonemorpha fragrans.

Strictosidine synthase (EC 4.3.3.2) is an enzyme in alkaloid biosynthesis that catalyses the condensation of tryptamine with secologanin to form strictosidine in a formal Pictet–Spengler reaction:

<span class="mw-page-title-main">Polyneuridine-aldehyde esterase</span>

The enzyme polyneuridine-aldehyde esterase (EC 3.1.1.78) catalyzes the following reaction:

In enzymology, a vinorine synthase is an enzyme that catalyzes the chemical reaction

<span class="mw-page-title-main">Ajmalan</span> Chemical compound

Ajmalan is a parent hydride used in the IUPAC nomenclature of natural products and also in CAS nomenclature. It is a 20-carbon alkaloid with six rings and seven chiral centres.

<span class="mw-page-title-main">Toxiferine</span> One of the most toxic plant alkaloids.

Toxiferine, also known as c-toxiferine I, is one of the most toxic plant alkaloids known. It is derived from several plant species, including Strychnos toxifera and Chondrodendron tomentosum. Historically, it has been used as an arrow poison by indigenous peoples in South America for its neuromuscular blocking properties, allowing them to paralyze animals during hunting, but also possibly kill due to paralysis of the respiratory muscles. Toxiferine functions as an acetylcholine receptor (AChR) antagonist. The paralysis caused by toxiferine can in turn be antagonized by neostigmine.

<span class="mw-page-title-main">Ajmalicine</span> Chemical compound

Ajmalicine, also known as δ-yohimbine or raubasine, is an antihypertensive drug used in the treatment of high blood pressure. 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. It is an alkaloid found naturally in various plants such as Rauvolfia spp., Catharanthus roseus, and Mitragyna speciosa.

The enzyme acetylajmaline esterase (EC 3.1.1.80, AAE, 2β(R)-17-O-acetylajmalan:acetylesterase, acetylajmalan esterase; systematic name 17-O-acetylajmaline O-acetylhydrolase) catalyses the following reactions:

3α(S)-strictosidine β-glucosidase (EC 3.2.1.105) is an enzyme with systematic name strictosidine β-D-glucohydrolase. It catalyses the following chemical reaction:

<span class="mw-page-title-main">Strictosidine</span> Chemical compound

Strictosidine is a natural chemical compound and is classified as a glucoalkaloid and a vinca alkaloid. It is formed by the Pictet–Spengler condensation reaction of tryptamine with secologanin, catalyzed by the enzyme strictosidine synthase. Thousands of strictosidine derivatives are sometimes referred to by the broad phrase of monoterpene indole alkaloids. Strictosidine is an intermediate in the biosynthesis of numerous pharmaceutically valuable metabolites including quinine, camptothecin, ajmalicine, serpentine, vinblastine, vincristine and mitragynine.

<span class="mw-page-title-main">Stemmadenine</span> Chemical compound

Stemmadenine is a terpene indole alkaloid. Stemmadenine is believed to be formed from preakuammicine by a carbon-carbon bond cleavage. Cleavage of a second carbon-carbon bond is thought to form dehydrosecodine. The enzymes forming stemmadenine and using it as a substrate remain unknown to date. It is thought to be intermediate compound in many different biosynthetic pathways such as in Aspidosperma species. Many alkaloids are proposed to be produced through intermediate stemmadenine. Some of them are:

<span class="mw-page-title-main">Vobasine</span> Chemical compound

Vobasine is a naturally occurring monoterpene indole alkaloid found in several species in the genus Tabernaemontana including Tabernaemontana divaricata.

<span class="mw-page-title-main">Vinervine</span> Vinca alkaloid

Vinervine is a monoterpene indole alkaloid of the Vinca sub-group. It is a derivative of akuammicine, with one additional hydroxy (OH) group in the indole portion, hence it is also known as 12-hydroxyakuammicine.

References

  1. ↑ Siddiqui S, Siddiqui RH (1931). "Chemical examination of the roots of Rauwolfia serpentina Benth". J. Indian Chem. Soc. 8: 667–80.
  2. ↑ Sandilvi AN (12 April 2003). "Salimuzzaman Siddiqui: pioneer of scientific research in Pakistan". Daily Dawn . Archived from the original on 2007-09-27.
  3. 1 2 3 Roberts MF, Wink M (1998). Alkaloids: Biochemistry, Ecology, and Medical applications. Plenum Press.
  4. ↑ Hinse C, Stöckigt J (July 2000). "The structure of the ring-opened N beta-propyl-ajmaline (Neo-Gilurytmal) at physiological pH is obviously responsible for its better absorption and bioavailability when compared with ajmaline (Gilurytmal)". Die Pharmazie. 55 (7): 531–532. PMID   10944783.
  5. ↑ Namjoshi OA, Cook JM (2016). "Sarpagine and Related Alkaloids". The Alkaloids: Chemistry and Biology. Vol. 76. pp. 63–169. doi:10.1016/bs.alkal.2015.08.002. ISBN   9780128046821. PMC   4864735 . PMID   26827883.
  6. ↑ Wu F, Kerčmar P, Zhang C, Stöckigt J (2015). "Sarpagan-Ajmalan-Type Indoles: Biosynthesis, Structural Biology, and Chemo-Enzymatic Significance". The Alkaloids. Chemistry and Biology. 76: 1–61. doi:10.1016/bs.alkal.2015.10.001. PMID   26827882.
  7. ↑ Turpin V, et al. (2020). "Biosynthetically Relevant Reactivity of Polyneuridine Aldehyde". European Journal of Organic Chemistry. 2020 (45): 6989–6991. doi:10.1002/ejoc.202000963. S2CID   225501365.
  8. ↑ Wu F, Kerčmar P, Zhang C, Stöckigt J (2015). "Sarpagan-Ajmalan-Type Indoles: Biosynthesis, Structural Biology, and Chemo-Enzymatic Significance". The Alkaloids. Chemistry and Biology. 76: 1–61. doi:10.1016/bs.alkal.2015.10.001. PMID   26827882.
  9. ↑ Wu F, Kerčmar P, Zhang C, Stöckigt J (2015). "Sarpagan-Ajmalan-Type Indoles: Biosynthesis, Structural Biology, and Chemo-Enzymatic Significance". The Alkaloids. Chemistry and Biology. 76: 1–61. doi:10.1016/bs.alkal.2015.10.001. PMID   26827882.
  10. ↑ "Ajmaleen 54 | Unani Medicine for High blood Pressure | Ajmal.pk". Dawakhana Hakim Ajmal Khan. 14 June 2019. Retrieved 2019-08-09.
  11. ↑ Kiesecker C, Zitron E, Lück S, Bloehs R, Scholz EP, Kathöfer S, et al. (December 2004). "Class Ia anti-arrhythmic drug ajmaline blocks HERG potassium channels: mode of action". Naunyn-Schmiedeberg's Archives of Pharmacology. 370 (6): 423–435. doi:10.1007/s00210-004-0976-8. PMID   15599706. S2CID   22310415.
  12. ↑ Hedley PL, Jørgensen P, Schlamowitz S, Moolman-Smook J, Kanters JK, Corfield VA, Christiansen M (September 2009). "The genetic basis of Brugada syndrome: a mutation update". Human Mutation. 30 (9): 1256–1266. doi: 10.1002/humu.21066 . PMID   19606473.
  13. ↑ Kusumoto FM, Bailey KR, Chaouki AS, Deshmukh AJ, Gautam S, Kim RJ, et al. (September 2018). "Systematic Review for the 2017 AHA/ACC/HRS Guideline for Management of Patients With Ventricular Arrhythmias and the Prevention of Sudden Cardiac Death: A Report of the American College of Cardiology/American Heart Association Task Force on Clinical Practice Guidelines and the Heart Rhythm Society". Circulation. 138 (13): e392–e414. doi: 10.1161/CIR.0000000000000550 . PMID   29084732.
  14. ↑ Rolf S, Bruns HJ, Wichter T, Kirchhof P, Ribbing M, Wasmer K, et al. (June 2003). "The ajmaline challenge in Brugada syndrome: diagnostic impact, safety, and recommended protocol". European Heart Journal. 24 (12): 1104–1112. doi: 10.1016/s0195-668x(03)00195-7 . PMID   12804924.
  15. ↑ Ciconte G, Monasky MM, Vicedomini G, Borrelli V, Giannelli L, Pappone C (October 2019). "Unusual response to ajmaline test in Brugada syndrome patient leads to extracorporeal membrane oxygenator support". Europace. 21 (10): 1574. doi:10.1093/europace/euz139. PMID   31157372.
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