aporphine

Many different derivatives of aporphine have been isolated from plants.{{cite journal | vauthors = Stévigny C, Bailly C, Quetin-Leclercq J | title = Cytotoxic and antitumor potentialities of aporphinoid alkaloids | journal = Current Medicinal Chemistry. Anti-Cancer Agents | volume = 5 | issue = 2 | pages = 173–182 | date = March 2005 | pmid = 15777224 | doi = 10.2174/1568011053174864 | hdl = 2078.1/10136 }} For example, many water lilies (Nymphaea species) produce aporphine alkaloids such as Nuciferine, nymphaeine, nymphaline, nupharine, α- and β-nupharidine.{{cite journal | vauthors = Oliver-Bever B | title = Medicinal plants in tropical West Africa. II. Plants acting on the nervous system | journal = Journal of Ethnopharmacology | volume = 7 | issue = 1 | pages = 1–93 | date = January 1983 | pmid = 6132025 | doi = 10.1016/0378-8741(83)90082-X }}

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.{{cite journal | vauthors = Hoet S, Stévigny C, Block S, Opperdoes F, Colson P, Baldeyrou B, Lansiaux A, Bailly C, Quetin-Leclercq J | display-authors = 6 | title = Alkaloids from Cassytha filiformis and related aporphines: antitrypanosomal activity, cytotoxicity, and interaction with DNA and topoisomerases | journal = Planta Medica | volume = 70 | issue = 5 | pages = 407–413 | date = May 2004 | pmid = 15124084 | doi = 10.1055/s-2004-818967 }}

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.{{cite journal | vauthors = Auffret M, Drapier S, Vérin M | title = The Many Faces of Apomorphine: Lessons from the Past and Challenges for the Future | journal = Drugs in R&D | volume = 18 | issue = 2 | pages = 91–107 | date = June 2018 | pmid = 29546602 | pmc = 5995787 | doi = 10.1007/s40268-018-0230-3 }}

File:Aporphines.png

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.{{cite journal | vauthors = Guardia J, Casas M, Prat G, Trujols J, Segura L, Sánchez-Turet M | title = The apomorphine test: a biological marker for heroin dependence disorder? | journal = Addiction Biology | volume = 7 | issue = 4 | pages = 421–426 | date = October 2002 | pmid = 14578019 | doi = 10.1080/1355621021000006206 | s2cid = 32386793 }}

Aporphine is a dopamine receptor agonist targeting the D1 and D2 receptors.{{cite journal | vauthors = Goldman ME, Kebabian JW | title = Aporphine enantiomers. Interactions with D-1 and D-2 dopamine receptors | journal = Molecular Pharmacology | volume = 25 | issue = 1 | pages = 18–23 | date = January 1984 | pmid = 6231468 }} 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 hyperplasia or coronary artery disease.{{cite book | vauthors = Anastasiadis AG, Droggin D, Davis AR, Salomon L, Shabsigh R | chapter = Male and Female Sexual Dysfunction: Epidemiology, Pathophysiology, Classifications, and Treatment. | title = Principles of Gender-Specific Medicine: Aporphine SL | date = January 2004 | pages = 573–585 | publisher = Academic Press | doi = 10.1016/B978-012440905-7/50321-2 | isbn = 978-0-12-440905-7 }}

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{{cite journal | vauthors = Neumeyer JL, Neustadt BR, Oh KH, Weinhardt KK, Boyce CB, Rosenberg FJ, Teiger DG | title = 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 = Journal of Medicinal Chemistry | volume = 16 | issue = 11 | pages = 1223–1228 | date = November 1973 | pmid = 4201182 | doi = 10.1021/jm00269a601 }} and Raminelli,{{Cite journal | vauthors = Muraca AC, Perecim GP, Rodrigues A, Raminelli C |date=2017-06-20 |title=Convergent Total Synthesis of (±)-Apomorphine via Benzyne Chemistry: Insights into the Mechanisms Involved in the Key Step |journal=Synthesis |volume=49 |issue=16 |pages=3546–3557 |doi=10.1055/s-0036-1588855 |issn=0039-7881}} Pukateine by Happel,{{cite journal | vauthors = Zymalkowski F, Happel KH | title = [The total synthesis of (plus minus)-pukatein] | journal = Chemische Berichte | volume = 102 | issue = 9 | pages = 2959–2966 | date = September 1969 | pmid = 5806148 | doi = 10.1002/cber.19691020910 }} Isocorydine by Di,{{Cite journal | vauthors = Zhong M, Jiang Y, Chen Y, Yan Q, Liu J, Di D |date=2015-11-01 |title=Asymmetric total synthesis of (S)-isocorydine |journal=Tetrahedron: Asymmetry |language=en |volume=26 |issue=20 |pages=1145–1149 |doi=10.1016/j.tetasy.2015.09.008 |issn=0957-4166}} Nuciferine and Oliveroline by Cuny,{{Cite journal | vauthors = Cuny GD |date=2004-02-10 |title=Intramolecular ortho-Arylation of Phenols Utilized in the Synthesis of the Aporphine Alkaloids (.+-.)-Lirinidine and (.+-.)-Nuciferine. |journal=ChemInform |volume=35 |issue=6 |doi=10.1002/chin.200406170 |issn=0931-7597}}{{cite journal | vauthors = Ku AF, Cuny GD | title = Synthetic studies of 7-oxygenated aporphine alkaloids: preparation of (-)-oliveroline, (-)-nornuciferidine, and derivatives | journal = Organic Letters | volume = 17 | issue = 5 | pages = 1134–1137 | date = March 2015 | pmid = 25710592 | doi = 10.1021/acs.orglett.5b00007 }} Glaucine by Meyers,{{Cite journal | vauthors = Gottlieb L, Meyers AI |date=October 1990 |title=An asymmetric synthesis of aporphine and related alkaloids via chiral formamidines. (+)-glaucine, (+)-homoglaucine, and (-)-8,9-didemethoxythalisopavine |journal=The Journal of Organic Chemistry |language=en |volume=55 |issue=21 |pages=5659–5662 |doi=10.1021/jo00308a029 |issn=0022-3263}} Dicentrine by Cava,{{Cite journal | vauthors = Cava MP, Stern P, Wakisaka K |date=1973-01-01 |title=An improved photochemical aporphine synthesis: New syntheses of dicentrine and cassameridine |journal=Tetrahedron |language=en |volume=29 |issue=15 |pages=2245–2249 |doi=10.1016/S0040-4020(01)93344-7 |issn=0040-4020}} and Lysicamine by Raminelli.{{cite journal | vauthors = Rossini AF, Muraca AC, Casagrande GA, Raminelli C | title = Total Syntheses of Aporphine Alkaloids via Benzyne Chemistry: An Approach to the Formation of Aporphine Cores | journal = The Journal of Organic Chemistry | volume = 80 | issue = 20 | pages = 10033–10040 | date = October 2015 | pmid = 26375603 | doi = 10.1021/acs.joc.5b01634 }}

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.{{cite book | vauthors = Wu YC | chapter = New research and development on the Formosan Annonaceous plants. Aporphinoids | title = Studies in natural products chemistry | date = 2006 | pages = 957–1023 | publisher = Elsevier }}

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.{{Cite web | author = US EPA National Center for Environmental Assessment|date=2009-03-15 |title=Synthesis and Structure-Activity Relationships of a Series of Aporphine Derivatives with Antiarrhythmic Activities and Acute Toxicity |url=https://hero.epa.gov/hero/index.cfm/reference/details/reference_id/7167107 |access-date=2022-03-17 |website=hero.epa.gov |language=en}}

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.{{Cite journal |date=November 2012 |title=Broad US patent issued to Dyadic International |journal=Focus on Catalysts |volume=2012 |issue=11 |pages=7 |doi=10.1016/s1351-4180(12)70458-0 |issn=1351-4180}}

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.{{Cite journal | vauthors = Chawra HS, Gupta G, Singh SK, Pathak S, Rawat S, Mishra A, Gilhotra RM |date=2021-11-30 |title=Phytochemical constituents, Ethno medicinal properties and Applications of Plant: Litsea glutinosa (Lour.) C.B. Robinson (Lauraceae) |journal=Research Journal of Pharmacy and Technology |pages=6113–6118 |doi=10.52711/0974-360x.2021.01062 |issn=0974-360X}}

(R)-Aporphine is a dopamine receptor D₁ antagonist with a K_i of 717nM{{cite journal | vauthors = Hedberg MH, Linnanen T, Jansen JM, Nordvall G, Hjorth S, Unelius L, Johansson AM | title = 11-substituted (R)-aporphines: synthesis, pharmacology, and modeling of D2A and 5-HT1A receptor interactions | journal = Journal of Medicinal Chemistry | volume = 39 | issue = 18 | pages = 3503–3513 | date = August 1996 | pmid = 8784448 | doi = 10.1021/jm960189i }} and a dopamine receptor D₂ antagonist with a K_i of 527nM.{{cite journal | vauthors = Linnanen T, Brisander M, Unelius L, Rosqvist S, Nordvall G, Hacksell U, Johansson AM | title = Atropisomeric derivatives of 2',6'-disubstituted (R)-11-phenylaporphine: selective serotonin 5-HT(7) receptor antagonists | journal = Journal of Medicinal Chemistry | volume = 44 | issue = 9 | pages = 1337–1340 | date = April 2001 | pmid = 11311055 | doi = 10.1021/jm0108505 }} Aporphine and its related alkaloids bulbocapnine, boldine, glaucine, and corytuberine are antipsychotic, exert naloxone-reversible antinociceptive activity and, except for corytuberine, are anticonvulsant.{{cite journal | vauthors = Zetler G | title = Neuroleptic-like, anticonvulsant and antinociceptive effects of aporphine alkaloids: bulbocapnine, corytuberine, boldine and glaucine | journal = Archives Internationales de Pharmacodynamie et de Therapie | volume = 296 | pages = 255–281 | year = 1988 | pmid = 2907279 }} 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.{{cite journal | vauthors = Baldessarini RJ, Campbell A, Ben-Jonathan N, Ellingboe J, Zong R, Neumeyer JL | title = Effects of aporphine isomers on rat prolactin | journal = Neuroscience Letters | volume = 176 | issue = 2 | pages = 269–271 | date = August 1994 | pmid = 7830962 | doi = 10.1016/0304-3940(94)90098-1 | s2cid = 38264784 }}

Aporphine is hydroxylated in the body to form apomorphine.{{cite journal | vauthors = Bertol E, Fineschi V, Karch SB, Mari F, Riezzo I | title = Nymphaea cults in ancient Egypt and the New World: a lesson in empirical pharmacology | journal = Journal of the Royal Society of Medicine | volume = 97 | issue = 2 | pages = 84–85 | date = February 2004 | pmid = 14749409 | pmc = 1079300 | doi = 10.1177/014107680409700214 }}

The Nymphaea species, particularly Nymphaea Caerulea, contains aporphine alkaloids and is utilized in various contexts.{{Cite web |last=Seligman |first=Sian |date=2023-01-13 |title=Blue Lotus Flower: Smoking, Tea & More |url=https://doubleblindmag.com/blue-lotus/ |access-date=2023-01-19 |website=DoubleBlind Mag |language=en-US}} 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.{{cite journal | vauthors = Schimpf M, Ulmer T, Hiller H, Barbuto AF | title = Toxicity From Blue Lotus (Nymphaea caerulea) After Ingestion or Inhalation: A Case Series | journal = Military Medicine | date = August 2021 | volume = 188 | issue = 7–8 | pages = e2689–e2692 | pmid = 34345890 | doi = 10.1093/milmed/usab328 | doi-access = free }}

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.{{cite journal | vauthors = Grünblatt E, Mandel S, Berkuzki T, Youdim MB | title = Apomorphine protects against MPTP-induced neurotoxicity in mice | journal = Movement Disorders | volume = 14 | issue = 4 | pages = 612–618 | date = July 1999 | pmid = 10435498 | doi = 10.1002/1531-8257(199907)14:4<612::aid-mds1010>3.0.co;2-6 }} Notably, apomorphine is used in veterinary clinics as an emetic due to severe off-target effects that lead to vomiting.{{cite journal | vauthors = Scott KA, Qureshi MH, Cox PB, Marshall CM, Bellaire BC, Wilcox M, Stuart BA, Njardarson JT | display-authors = 6 | title = A Structural Analysis of the FDA Green Book-Approved Veterinary Drugs and Roles in Human Medicine | journal = Journal of Medicinal Chemistry | volume = 63 | issue = 24 | pages = 15449–15482 | date = December 2020 | pmid = 33125236 | doi = 10.1021/acs.jmedchem.0c01502 | s2cid = 226218045 }}

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.{{cite journal | vauthors = Picada JN, Flores DG, Zettler CG, Marroni NP, Roesler R, Henriques JA | title = DNA damage in brain cells of mice treated with an oxidized form of apomorphine | journal = Brain Research. Molecular Brain Research | volume = 114 | issue = 1 | pages = 80–85 | date = May 2003 | pmid = 12782396 | doi = 10.1016/s0169-328x(03)00127-x }}

• Anonaine
• Liriodenine
• Magnoflorine
• Nantenine
• Nuciferine

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