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Aporphine

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Aporphine is an alkaloid with the chemical formula C17H17N. It is the core chemical substructure of the aporphine alkaloids, a subclass of quinoline alkaloids. It can exist in either of two enantiomeric forms, (R)-aporphine and (S)-aporphine.

Aporphine
Identifiers
  • 6-methyl-5,6,6a,7-tetrahydro-4H-dibenzo[de,g]quinoline
CAS Number
PubChem CID
ChemSpider
UNII
ChEBI
CompTox Dashboard (EPA)
Chemical and physical data
FormulaC17H17N
Molar mass235.330 g·mol−1
3D model (JSmol)
  • c12c(cccc1)CC4c3c(cccc23)CCN4C
  • InChI=1S/C17H17N/c1-18-10-9-12-6-4-8-15-14-7-3-2-5-13(14)11-16(18)17(12)15/h2-8,16H,9-11H2,1H3
  • Key:BZKUYNBAFQJRDM-UHFFFAOYSA-N

Derivatives

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Many different derivatives of aporphine have been isolated from plants.[1] For example, many water lilies (Nymphaea species) produce aporphine alkaloids such as nymphaeine, nymphaline, nupharine, α- and β-nupharidine.[2]

In vitro, tests of some aporphine derivatives isolated from Cassytha filiformis, namely, actinodaphnine, cassythine, and dicentrine, showed antiparasitic activity against Trypanosoma brucei. Investigation of possible mechanisms revealed that the compounds bind to DNA and act as intercalating agents, in addition to inhibiting topoisomerase activity.[3]

Aporphine natural products occur with either the (R)- or (S)- isomeric forms, or they can be achiral. Furthermore, morphine-based natural products can be heated in acid to give aporphine degradation products; one example is the FDA-approved Parkinson's drug apomorphine, which was first discovered by the Finnish chemist Adolf Edvard Arppe in 1845.[4]

 
Aporphines can occur as either (R)- or (S)-isomers, or as achiral compounds, and while many of these are toxic, some have been used for their medicinal value and have been approved by the FDA and world markets.

Apomorphine

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Apomorphine is a derivative of aporphine. The compound is historically obtained by heating morphine with hydrochloric acid. Contrary to its name, apomorphine does not contain morphine or its skeleton, nor does it bind to opioid receptors. The apo- prefix indicates that it is a morphine derivative.

Historically, apomorphine has seen a variety of clinical uses including as a treatment for anxiety and cravings in alcoholics, as an emetic, and more recently in treating erectile dysfunction. It was also used as a private treatment for heroin addiction. Still, there is no clinical evidence that apomorphine is an effective and safe treatment for opiate addiction.

Currently, apomorphine is used in the treatment of Parkinson's disease. It is a potent emetic, typically administered with an antiemetic such as domperidone. Apomorphine is also utilized in veterinary medicine to induce therapeutic emesis in canines that have recently ingested toxic or foreign substances.[5]

Effects

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Aporphine is a dopamine receptor agonist targeting the D1 and D2 receptors.[6] In rodents, aporphine administration has been demonstrated to activate gene expression, specifically in the nuclei of the hypothalamus, resulting in stereotypical behavior of erection and yawning. In humans, aporphine produces nonsexual erections that are enhanced by erotic stimulation without changes in libido, but significant side effects can occur. A sublingual formulation of aporphine 2-4 mg with a rapid onset of action has been developed, proven to be efficacious in erectile dysfunction patients with controlled diabetes, hypertension, benign prostatic hypertrophy or coronary vascular disease.[7]

Synthesis

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Aporphine and its derivatives can be obtained through various synthetic methods.

Several natural products including semisynthetic analogs belonging to the aporphine class have been synthesized. These include apomorphine by Neumeyer[8] and Raminelli,[9] Pukateine by Happel,[10] Isocorydine by Di,[11] Nuciferine and Oliveroline by Cuny,[12][13] Glaucine by Meyers,[14] Dicentrine by Cava,[15] and Lysicamine by Raminelli.[16]

Toxicity

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Most aporphine alkaloids are toxic and typically exhibit antagonistic effects to dopamine. Many of them have anticonvulsant activity or induce convulsions in animals due to cytotoxic activity.[17]

Some aporphine alkaloids (such as crebanine) have been found to present arrhythmic activity and higher toxicity. In one study, a couple of target derivatives were evaluated for their anti-arrhythmic potential in the mouse model of ventricular fibrillation. Here, preliminary structure-activity/toxicity relationship analyses were carried out. Of these target derivatives, a certain bromo-substituted product of crebanine displayed significant anti-arrhythmic activity and a lower toxicity. In a significant number of rats, this product caused reduction in the incidence of VF, increase in the resumption of sinus rhythm from arrhythmia, and increase in maintaining sinus rhythm. The results from this limited study indicate that this specific aporphine alkaloid could be considered as a promising candidate in the treatment of arrhythmia.[18]

Pharmacology

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According to the U.S. Patent & Trademark Office, aporphine derivatives can treat oxidative stress-induced diseases. Specifically, it inhibits lipid peroxidase and performs free radical-scavenging activities, thereby exhibiting a protective effect on endothelial cells. This reduces oxidative stress which may induce diseases such as cardiovascular disease, Alzheimer's disease, kidney disease, diabetes, cancer etc.[19]

Aporphine alkaloids present in Litsea glutinosa, a tropical plant with antioxidant and anti-parasitic properties, are claimed to contribute to anti-cancer activity. Research has illustrated the antiproliferative and cytotoxic effects of aporphine-containing extracts of Litsea glutinosa.[20]

(R)-Aporphine is a dopamine receptor D1 antagonist with a Ki of 717nM[21] and a dopamine receptor D2 antagonist with a Ki of 527nM.[22] Aporphine and its related alkaloids bulbocapnine, boldine, glaucine, and corytuberine are antipsychotic, exert naloxone-reversible antinociceptive activity and, except for corytuberine, are anticonvulsant.[23] Some derivatives of aporphine such as (S)-(+)-N-propylnorapomorphine have potential as low side effect profile antipsychotics. (S)-(+)-N-Propylnorapomorphine is highly selective for meso-limbic dopaminergic tracts and function as efficacious partial agonists, with no elevation in prolactin.[24]

Pharmacokinetics

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Aporphine is hydroxylated in the body to form apomorphine.[25]

Psychoactive effects

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The Nymphaea species, particularly Nymphaea Caerulea, contains aporphine alkaloids and is utilized in various contexts.[26] Extracts of this plant when ingested or smoken in high doses are reported to produce euphoria and hallucinations. Commonly known as the blue lotus, Nymphaea Caerulea is available in several forms, including dried plant material, teas, and extracts for electronic cigarettes. The psychoactive effects of the flower are attributed to two aporphine alkaloids: apomorphine and nuciferine. These compounds have mixed effects on serotonin and dopamine receptors, functioning as a dopaminergic agonist.[27]

Effects on animals

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There are no studies on aporphine in animals. However, studies on subcutaneous apomorphine injection, the bioactive form of aporphine, have been carried out. In a 5-day study, mice were administered up to 10 mg/kg apomorphine subcutaneously daily. No adverse effects were observed other than a slight increase in dopamine levels.[28] Notably, apomorphine is used in veterinary clinics as an emetic due to severe off-target effects that lead to vomiting.[29]

In another study, mice were administered a single 40 mg/kg dose of apomorphine. Slight DNA damage was observed in brain tissue three hours after treatment.[30]

See also

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References

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  1. ^ Stévigny C, Bailly C, Quetin-Leclercq J (March 2005). "Cytotoxic and antitumor potentialities of aporphinoid alkaloids". Current Medicinal Chemistry. Anti-Cancer Agents. 5 (2): 173–182. doi:10.2174/1568011053174864. hdl:2078.1/10136. PMID 15777224.
  2. ^ Oliver-Bever B (January 1983). "Medicinal plants in tropical West Africa. II. Plants acting on the nervous system". Journal of Ethnopharmacology. 7 (1): 1–93. doi:10.1016/0378-8741(83)90082-X. PMID 6132025.
  3. ^ Hoet S, Stévigny C, Block S, Opperdoes F, Colson P, Baldeyrou B, et al. (May 2004). "Alkaloids from Cassytha filiformis and related aporphines: antitrypanosomal activity, cytotoxicity, and interaction with DNA and topoisomerases". Planta Medica. 70 (5): 407–413. doi:10.1055/s-2004-818967. PMID 15124084.
  4. ^ Auffret M, Drapier S, Vérin M (June 2018). "The Many Faces of Apomorphine: Lessons from the Past and Challenges for the Future". Drugs in R&D. 18 (2): 91–107. doi:10.1007/s40268-018-0230-3. PMC 5995787. PMID 29546602.
  5. ^ Guardia J, Casas M, Prat G, Trujols J, Segura L, Sánchez-Turet M (October 2002). "The apomorphine test: a biological marker for heroin dependence disorder?". Addiction Biology. 7 (4): 421–426. doi:10.1080/1355621021000006206. PMID 14578019. S2CID 32386793.
  6. ^ Goldman ME, Kebabian JW (January 1984). "Aporphine enantiomers. Interactions with D-1 and D-2 dopamine receptors". Molecular Pharmacology. 25 (1): 18–23. PMID 6231468.
  7. ^ Anastasiadis AG, Droggin D, Davis AR, Salomon L, Shabsigh R (January 2004). "Male and Female Sexual Dysfunction: Epidemiology, Pathophysiology, Classifications, and Treatment.". Principles of Gender-Specific Medicine: Aporphine SL. Academic Press. pp. 573–585. doi:10.1016/B978-012440905-7/50321-2. ISBN 978-0-12-440905-7.
  8. ^ Neumeyer JL, Neustadt BR, Oh KH, Weinhardt KK, Boyce CB, Rosenberg FJ, Teiger DG (November 1973). "Aporphines. 8. Total synthesis and pharmacological evaluation of (plus or minus)-apomorphine, (plus or minus)-apocodeine, (plus or minus)-N-n-propylnorapomorphine, and (plus or minus)-N-n-propylnorapocodeine". Journal of Medicinal Chemistry. 16 (11): 1223–1228. doi:10.1021/jm00269a601. PMID 4201182.
  9. ^ Muraca AC, Perecim GP, Rodrigues A, Raminelli C (2017-06-20). "Convergent Total Synthesis of (±)-Apomorphine via Benzyne Chemistry: Insights into the Mechanisms Involved in the Key Step". Synthesis. 49 (16): 3546–3557. doi:10.1055/s-0036-1588855. ISSN 0039-7881.
  10. ^ Zymalkowski F, Happel KH (September 1969). "[The total synthesis of (plus minus)-pukatein]". Chemische Berichte. 102 (9): 2959–2966. doi:10.1002/cber.19691020910. PMID 5806148.
  11. ^ Zhong M, Jiang Y, Chen Y, Yan Q, Liu J, Di D (2015-11-01). "Asymmetric total synthesis of (S)-isocorydine". Tetrahedron: Asymmetry. 26 (20): 1145–1149. doi:10.1016/j.tetasy.2015.09.008. ISSN 0957-4166.
  12. ^ Cuny GD (2004-02-10). "Intramolecular ortho-Arylation of Phenols Utilized in the Synthesis of the Aporphine Alkaloids (.+-.)-Lirinidine and (.+-.)-Nuciferine". ChemInform. 35 (6). doi:10.1002/chin.200406170. ISSN 0931-7597.
  13. ^ Ku AF, Cuny GD (March 2015). "Synthetic studies of 7-oxygenated aporphine alkaloids: preparation of (-)-oliveroline, (-)-nornuciferidine, and derivatives". Organic Letters. 17 (5): 1134–1137. doi:10.1021/acs.orglett.5b00007. PMID 25710592.
  14. ^ Gottlieb L, Meyers AI (October 1990). "An asymmetric synthesis of aporphine and related alkaloids via chiral formamidines. (+)-glaucine, (+)-homoglaucine, and (-)-8,9-didemethoxythalisopavine". The Journal of Organic Chemistry. 55 (21): 5659–5662. doi:10.1021/jo00308a029. ISSN 0022-3263.
  15. ^ Cava MP, Stern P, Wakisaka K (1973-01-01). "An improved photochemical aporphine synthesis: New syntheses of dicentrine and cassameridine". Tetrahedron. 29 (15): 2245–2249. doi:10.1016/S0040-4020(01)93344-7. ISSN 0040-4020.
  16. ^ Rossini AF, Muraca AC, Casagrande GA, Raminelli C (October 2015). "Total Syntheses of Aporphine Alkaloids via Benzyne Chemistry: An Approach to the Formation of Aporphine Cores". The Journal of Organic Chemistry. 80 (20): 10033–10040. doi:10.1021/acs.joc.5b01634. PMID 26375603.
  17. ^ Wu YC (2006). "New research and development on the Formosan Annonaceous plants. Aporphinoids". Studies in natural products chemistry. Elsevier. pp. 957–1023.
  18. ^ US EPA National Center for Environmental Assessment (2009-03-15). "Synthesis and Structure-Activity Relationships of a Series of Aporphine Derivatives with Antiarrhythmic Activities and Acute Toxicity". hero.epa.gov. Retrieved 2022-03-17.
  19. ^ "Broad US patent issued to Dyadic International". Focus on Catalysts. 2012 (11): 7. November 2012. doi:10.1016/s1351-4180(12)70458-0. ISSN 1351-4180.
  20. ^ Chawra HS, Gupta G, Singh SK, Pathak S, Rawat S, Mishra A, Gilhotra RM (2021-11-30). "Phytochemical constituents, Ethno medicinal properties and Applications of Plant: Litsea glutinosa (Lour.) C.B. Robinson (Lauraceae)". Research Journal of Pharmacy and Technology: 6113–6118. doi:10.52711/0974-360x.2021.01062. ISSN 0974-360X.
  21. ^ Hedberg MH, Linnanen T, Jansen JM, Nordvall G, Hjorth S, Unelius L, Johansson AM (August 1996). "11-substituted (R)-aporphines: synthesis, pharmacology, and modeling of D2A and 5-HT1A receptor interactions". Journal of Medicinal Chemistry. 39 (18): 3503–3513. doi:10.1021/jm960189i. PMID 8784448.
  22. ^ Linnanen T, Brisander M, Unelius L, Rosqvist S, Nordvall G, Hacksell U, Johansson AM (April 2001). "Atropisomeric derivatives of 2',6'-disubstituted (R)-11-phenylaporphine: selective serotonin 5-HT(7) receptor antagonists". Journal of Medicinal Chemistry. 44 (9): 1337–1340. doi:10.1021/jm0108505. PMID 11311055.
  23. ^ Zetler G (1988). "Neuroleptic-like, anticonvulsant and antinociceptive effects of aporphine alkaloids: bulbocapnine, corytuberine, boldine and glaucine". Archives Internationales de Pharmacodynamie et de Therapie. 296: 255–281. PMID 2907279.
  24. ^ Baldessarini RJ, Campbell A, Ben-Jonathan N, Ellingboe J, Zong R, Neumeyer JL (August 1994). "Effects of aporphine isomers on rat prolactin". Neuroscience Letters. 176 (2): 269–271. doi:10.1016/0304-3940(94)90098-1. PMID 7830962. S2CID 38264784.
  25. ^ Bertol E, Fineschi V, Karch SB, Mari F, Riezzo I (February 2004). "Nymphaea cults in ancient Egypt and the New World: a lesson in empirical pharmacology". Journal of the Royal Society of Medicine. 97 (2): 84–85. doi:10.1177/014107680409700214. PMC 1079300. PMID 14749409.
  26. ^ Seligman, Sian (2023-01-13). "Blue Lotus Flower: Smoking, Tea & More". DoubleBlind Mag. Retrieved 2023-01-19.
  27. ^ Schimpf M, Ulmer T, Hiller H, Barbuto AF (August 2021). "Toxicity From Blue Lotus (Nymphaea caerulea) After Ingestion or Inhalation: A Case Series". Military Medicine. 188 (7–8): e2689–e2692. doi:10.1093/milmed/usab328. PMID 34345890.
  28. ^ Grünblatt E, Mandel S, Berkuzki T, Youdim MB (July 1999). "Apomorphine protects against MPTP-induced neurotoxicity in mice". Movement Disorders. 14 (4): 612–618. doi:10.1002/1531-8257(199907)14:4<612::aid-mds1010>3.0.co;2-6. PMID 10435498.
  29. ^ Scott KA, Qureshi MH, Cox PB, Marshall CM, Bellaire BC, Wilcox M, et al. (December 2020). "A Structural Analysis of the FDA Green Book-Approved Veterinary Drugs and Roles in Human Medicine". Journal of Medicinal Chemistry. 63 (24): 15449–15482. doi:10.1021/acs.jmedchem.0c01502. PMID 33125236. S2CID 226218045.
  30. ^ Picada JN, Flores DG, Zettler CG, Marroni NP, Roesler R, Henriques JA (May 2003). "DNA damage in brain cells of mice treated with an oxidized form of apomorphine". Brain Research. Molecular Brain Research. 114 (1): 80–85. doi:10.1016/s0169-328x(03)00127-x. PMID 12782396.
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