Aporphine is analkaloid with the chemical formulaC17H17N. It is the core chemical substructure of theaporphine alkaloids, a subclass ofquinoline alkaloids. It can exist in either of twoenantiomeric forms, (R)-aporphine and (S)-aporphine.
Many differentderivatives of aporphine have been isolated from plants.[1] For example, manywater lilies (Nymphaea species) produce aporphine alkaloids such asNuciferine, nymphaeine, nymphaline, nupharine, α- and β-nupharidine.[2]
Aporphine natural products occur with either the (R)- or (S)-isomeric forms, or they can beachiral. 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 is a derivative of aporphine. The compound is historically obtained by heating morphine withhydrochloric acid. Contrary to its name, apomorphine does not contain morphine or its skeleton, nor does it bind toopioid receptors. The apo- prefix indicates that it is a morphine derivative.
Historically, apomorphine has seen a variety of clinical uses including as a treatment foranxiety and cravings in alcoholics, as anemetic, and more recently in treatingerectile 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 foropiate addiction.
Currently, apomorphine is used in the treatment ofParkinson's disease. It is a potentemetic, typically administered with an antiemetic such asdomperidone. Apomorphine is also utilized inveterinary medicine to induce therapeuticemesis in canines that have recently ingested toxic or foreign substances.[5]
Aporphine is adopamine receptor agonist targeting theD1 andD2 receptors.[6] In rodents, aporphine administration has been demonstrated to activategene expression, specifically in the nuclei of thehypothalamus, 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 controlleddiabetes,hypertension,benign prostatic hyperplasia orcoronary artery disease.[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[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]
Most aporphinealkaloids are toxic and typically exhibit antagonistic effects to dopamine. Many of them have anticonvulsant activity or induce convulsions in animals due tocytotoxic activity.[17]
Some aporphine alkaloids (such as crebanine) have been found to presentarrhythmic activity and higher toxicity. In one study, a couple of target derivatives were evaluated for their anti-arrhythmic potential in the mouse model ofventricular 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 ofsinus 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]
According to the U.S. Patent & Trademark Office, aporphine derivatives can treat oxidative stress-induced diseases. Specifically, it inhibits lipidperoxidase and performs free radical-scavenging activities, thereby exhibiting a protective effect onendothelial 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 inLitsea glutinosa, a tropical plant with antioxidant and anti-parasitic properties, are claimed to contribute to anti-cancer activity. Research has illustrated theantiproliferative and cytotoxic effects of aporphine-containing extracts of Litsea glutinosa.[20]
(R)-Aporphine is adopamine receptor D1 antagonist with aKi of 717nM[21] and adopamine receptor D2 antagonist with aKi of 527nM.[22] Aporphine and its related alkaloidsbulbocapnine,boldine,glaucine, and corytuberine are antipsychotic, exertnaloxone-reversibleantinociceptive 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 formeso-limbic dopaminergic tracts and function as efficacious partial agonists, with no elevation in prolactin.[24]
TheNymphaea species, particularlyNymphaea 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 produceeuphoria andhallucinations. Commonly known as the blue lotus,Nymphaea Caerulea is available in several forms, including dried plant material,teas, and extracts forelectronic cigarettes. The psychoactive effects of the flower are attributed to two aporphine alkaloids: apomorphine andnuciferine. These compounds have mixed effects onserotonin anddopamine receptors, functioning as a dopaminergic agonist.[27]
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]
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^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.ISBN978-0-12-440905-7.
^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.PMID4201182.
^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.ISSN0039-7881.
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^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.ISSN0931-7597.
^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.PMID25710592.
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