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| Formula | C17H17N |
| Molar mass | 235.330 g·mol−1 |
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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.
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]
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]
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]
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 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]
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]
Aporphine is hydroxylated in the body to form apomorphine. [25]
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]
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]
Ergoline is a chemical compound whose structural skeleton is contained in a variety of alkaloids, referred to as ergoline derivatives or ergoline alkaloids. Ergoline alkaloids, one being ergine, were initially characterized in ergot. Some of these are implicated in the condition ergotism, which can take a convulsive form or a gangrenous form. Even so, many ergoline alkaloids have been found to be clinically useful. Annual world production of ergot alkaloids has been estimated at 5,000–8,000 kg of all ergopeptines and 10,000–15,000 kg of lysergic acid, used primarily in the manufacture of semi-synthetic derivatives.
Epibatidine is a chlorinated alkaloid that is secreted by the Ecuadoran frog Epipedobates anthonyi and poison dart frogs from the Ameerega genus. It was discovered by John W. Daly in 1974, but its structure was not fully elucidated until 1992. Whether epibatidine is the first observed example of a chlorinated alkaloid remains controversial, due to challenges in conclusively identifying the compound from the limited samples collected by Daly. By the time that high-resolution spectrometry was used in 1991, there remained less than one milligram of extract from Daly's samples, raising concerns about possible contamination. Samples from other batches of the same species of frog failed to yield epibatidine.
Apomorphine, sold under the brand name Apokyn among others, is a type of aporphine having activity as a non-selective dopamine agonist which activates both D2-like and, to a much lesser extent, D1-like receptors. It also acts as an antagonist of 5-HT2 and α-adrenergic receptors with high affinity. The compound is historically a morphine decomposition product made by boiling morphine with concentrated acid, hence the -morphine suffix. Contrary to its name, apomorphine does not actually contain morphine or its skeleton, nor does it bind to opioid receptors. The apo- prefix relates to it being a morphine derivative ("[comes] from morphine").
A dopamine agonist is a compound that activates dopamine receptors. There are two families of dopamine receptors, D1-like and D2-like. They are all G protein-coupled receptors. D1- and D5-receptors belong to the D1-like family and the D2-like family includes D2, D3 and D4 receptors. Dopamine agonists are primarily used in the treatment of the motor symptoms of Parkinson's disease, and to a lesser extent, in hyperprolactinemia and restless legs syndrome. They are also used off-label in the treatment of clinical depression. Impulse control disorders are associated with the use of dopamine agonists for whatever condition.
WIN 35,428 is a stimulant drug used in scientific research. CFT is a phenyltropane based dopamine reuptake inhibitor and is structurally derived from cocaine. It is around 3-10x more potent than cocaine and lasts around 7 times longer based on animal studies. While the naphthalenedisulfonate salt is the most commonly used form in scientific research due to its high solubility in water, the free base and hydrochloride salts are known compounds and can also be produced. The tartrate is another salt form that is reported.
18-Methoxycoronaridine, also known as zolunicant, is a derivative of ibogaine invented in 1996 by the research team around the pharmacologist Stanley D. Glick from the Albany Medical College and the chemists Upul K. Bandarage and Martin E. Kuehne from the University of Vermont. In animal studies it has proven to be effective at reducing self-administration of morphine, cocaine, methamphetamine, nicotine and sucrose. It has also been shown to produce anorectic effects in obese rats, most likely due to the same actions on the reward system which underlie its anti-addictive effects against drug addiction.
Troparil is a stimulant drug used in scientific research. Troparil is a phenyltropane-based dopamine reuptake inhibitor (DRI) that is derived from methylecgonidine. Troparil is a few times more potent than cocaine as a dopamine reuptake inhibitor, but is less potent as a serotonin reuptake inhibitor, and has a duration spanning a few times longer, since the phenyl ring is directly connected to the tropane ring through a non-hydrolyzable carbon-carbon bond. The lack of an ester linkage removes the local anesthetic action from the drug, so troparil is a pure stimulant. This change in activity also makes troparil slightly less cardiotoxic than cocaine. The most commonly used form of troparil is the tartrate salt, but the hydrochloride and naphthalenedisulfonate salts are also available, as well as the free base.
Nuciferine is an alkaloid found within the plants Nymphaea caerulea and Nelumbo nucifera.
Dopamine receptor D3 is a protein that in humans is encoded by the DRD3 gene.
N-n-Propylnorapomorphine (NPA) is an aporphine derivative dopamine agonist closely related to apomorphine. In rodents it has been shown to produce hyperactivity, stereotypy, hypothermia, antinociception, and penile erection, among other effects. Notably, its effects on locomotion are biphasic, with low doses producing inhibition and catalepsy and high doses resulting in enhancement of activity. This is likely due to preferential activation of D2/D3 autoreceptors versus postsynaptic receptors, the latter of which overcomes the former to increase postsynaptic dopaminergic signaling only with high doses.
Epiboxidine is a chemical compound which acts as a partial agonist at neural nicotinic acetylcholine receptors, binding to both the α3β4 and the α4β2 subtypes. It was developed as a less toxic analogue of the potent frog-derived alkaloid epibatidine, which is around 200 times stronger than morphine as an analgesic but produces extremely dangerous toxic nicotinic side effects.
Glaucine(1,2,9,10-TetraMethoxyAporphine, Bromcholitin, Glauvent, Tusidil, Tussiglaucin) is an aporphine alkaloid found in several different plant species in the family Papaveraceae such as Glaucium flavum, Glaucium oxylobum and Corydalis yanhusuo, and in other plants like Croton lechleri in the family Euphorbiaceae.
Tetrahydropalmatine (THP) is an isoquinoline alkaloid found in several different plant species, mainly in the genus Corydalis, but also in other plants such as Stephania rotunda. These plants have traditional uses in Chinese herbal medicine. The pharmaceutical industry has synthetically produced the more potent enantiomer Levo-tetrahydropalmatine (Levo-THP), which has been marketed worldwide under different brand names as an alternative to anxiolytic and sedative drugs of the benzodiazepine group and analgesics such as opiates. It is also sold as a dietary supplement.
(−)-Stepholidine is a protoberberine alkaloid found in the plant Stephania intermedia.
Arylcyclohexylamines, also known as arylcyclohexamines or arylcyclohexanamines, are a chemical class of pharmaceutical, designer, and experimental drugs.
Tabernanthine is an alkaloid found in Tabernanthe iboga.
Sonepiprazole (U-101,387, PNU-101,387-G) is a drug of the phenylpiperazine class which acts as a highly selective D4 receptor antagonist. In animals, unlike D2 receptor antagonists like haloperidol, sonepiprazole does not block the behavioral effects of amphetamine or apomorphine, does not alter spontaneous locomotor activity on its own, and lacks extrapyramidal and neuroendocrine effects. However, it does reverse the prepulse inhibition deficits induced by apomorphine, and has also been shown to enhance cortical activity and inhibit stress-induced cognitive impairment. As a result, it was investigated as an antipsychotic for the treatment of schizophrenia in a placebo-controlled clinical trial, but in contrast to its comparator olanzapine no benefits were found and it was not researched further for this indication.
SB-206553 is a drug which acts as a mixed antagonist for the 5-HT2B and 5-HT2C serotonin receptors. It has anxiolytic properties in animal studies and interacts with a range of other drugs. It has also been shown to act as a positive allosteric modulator of α7 nicotinic acetylcholine receptors. Modified derivatives of SB-206553 have been used to probe the structure of the 5-HT2B receptor.
Iboga-type alkaloids are a set of monoterpene indole alkaloids comprising naturally occurring compounds found in Tabernanthe and Tabernaemontana, as well as synthetic structural analogs. Naturally occurring iboga-type alkaloids include ibogamine, ibogaine, tabernanthine, and other substituted ibogamines. Many iboga-type alkaloids display biological activities such as cardiac toxicity and psychoactive effects, and some have been studied as potential treatments for drug addiction.
Aporphine alkaloids are naturally occurring chemical compounds from the group of alkaloids. After the benzylisoquinoline alkaloids they are the second largest group of isoquinoline alkaloids.
