Apomorphine

Biological Effects

Apomorphine is an agonist, or activator, of both D₁ and D₂ type dopamine receptors with a preference toward the D₂ group. The members of the D₂ subfamily, consisting of D₂, D₃, and D₄ receptors, are involved with inhibitory neurotransmission. Inhibition is achieved through a signaling pathway in which the activated receptor, a G protein–coupled receptor, inhibits the enzyme adenylate cyclase, therefore decreasing the levels of the signaling molecule cyclic AMP. The D₄ receptor in particular is an important target in the signaling pathway, and is connected to several neurological disorders. Shortage or excess of dopamine can prevent proper function and signaling of these receptors leading to disease states. It is classically thought that an excess of dopamine stimulation is a factor in schizophrenia, but it appears this relationship is pathway dependent and just one of several contributing factors. Apomorphine is useful in diseases where dopamine levels are lower than normal, such as Parkinson’s disease, and can help to restore proper motor behavior by increasing the inhibitory signaling.

Alcoholism

Apomorphine was used with some notable success as a treatment for alcohol and morphine addiction. At first this was part of a Pavlov style "conditioned-reflex" treatment, later continued with emetine by practitioners such as Voegtlin in the US, but gradually this was replaced by a recognition by various practitioners in Europe that the drug was having other effects. However, this form treatment fell out of favour, and was over by the 1980s.

Parkinson's disease

First used as a treatment for Parkinson's disease as early as 1951, its clinical use was first reported in 1970 by Cotzias et al., although its emetic properties and short half-life made oral use impractical. A later study found that combining the drug with the antiemetic domperidone improved results significantly. The commercialization of apomorphine for Parkinson's disease followed its successful use in patients with refractory motor fluctuations using intermittent rescue injections and continuous infusions.

Therapeutic use in Parkinson's disease is effective because of the drug's strong dopaminergic action. When administered subcutaneously, apomorphine is the most effective dopamine agonist. Within 3–20 minutes of injection apomorphine demonstrates a magnitude of effect (ability to convert the patient with Parkinson's disease to the "on" state) that is comparable to L-DOPA. A single subcutaneous injection lasts for up to 90 minutes. While apomorphine can be used in combination with L-DOPA, the intention is usually to reduce the L-DOPA dosing, as by this stage the patient with Parkinson's disease will probably be experiencing a great deal of dopa-induced dyskinesias and "off" periods. Following a successful apomorphine challenge, training of patient and caregiver, and careful dose titration, the patient can be maintained in the "on" state by the use of an apomorphine pump as an effective monotherapy.

Erectile dysfunction

Apomorphine hydrochloride (trade name "Uprima", "Ixense") was a therapy used in the treatment of erectile dysfunction (male impotence). It is its mode of stimulating dopamine in the brain which is believed to enhance the sexual response. It was found to be of poor efficacy in a large-scale study by Researchers at the UK's Drug Safety Research Unit and University of Portsmouth and discontinued in the UK in January 2006. Around 65-70% of doctors felt it was ineffective, with 60% of over 11,000 patients (average age 61) discontinuing in month 1 and a further 23% in month 2. UK studies concentrated on males with generalized erectile dysfunction. Uprima affects desire and is not meant to produce a systemic effect unlike drugs such as sildenafil, which affect circulation. In those males who have problems with desire as opposed to generalized erectile dysfunction, it works as expected.

Erections in men are generally classified into two categories: Reflexogenic erections, that is erections triggered by physical stimulus of the penis, and Psychogenic erections, which are triggered by sexual fantasies, thoughts and looking at things which are sexually stimulating. Psychogenic erections are generally gradually lost in men somewhere between the ages of 45 and 65. Apomorphine has been shown to restore Psychogenic erections in men who are otherwise unable to achieve them.

Alzheimer's disease

When proteins in a cell undergo misfolding due to damage, misprocessing, or mutation it can lead to the alteration of the protein’s secondary structure and change which amino acid residues are accessible. In many cases of protein aggregation, hydrophobic residues, which are normally on the interior of soluble proteins, become arranged so they are on the solvent exposed surface. This can lead to interactions between hydrophobic regions of multiple proteins, as it is entropically favorable to reduce the surface area of hydrophobicity exposed. The formation of a few molecules to form an oligomer is still soluble, but as it grows and continues to aggregate the product will fall out of solution, causing damage to the cell manifesting in proteopathic diseases. Recent studies have shown the pre-fibril aggregates are also toxic through their hydrophobic interactions with various cellular components causing cytoskeletal rearrangements and loss of cell-to-cell contacts.

Apomorphine is reported to be an inhibitor of amyloid beta protein (Aβ) fiber formation and a potential therapeutic for Alzheimer's disease (AD) under the amyloid hypothesis. Apomorphine and its small molecule relatives are found to promote oligomerization of the Aβ40 group of molecules, but inhibit the more advanced fibril formation from occurring. The mechanism of protection offered by the small molecules is thought to be due to the autoxidation that occurs at the hydroxyl groups. Once this functional group was altered, the inhibitory effect could be seen to decrease, reducing either the indirect or direct interference of the fibril formation.

The protective effects of apomorphine were tested in mouse models with mutations in genes related to AD, such as the amyloid precursor protein (APP) gene, which is implicated in amyloid molecule build-up. Apomorphine was seen to significantly improve memory function through the increased successful completion of the Morris Water Maze. The levels of the aberrant proteins that lead to neuronal disruption were also tested in the brains of mice. Treatment was seen to decrease the intraneuronal levels of the more aggressive Aβ42 molecule when compared to the control mice. This result is consistent with the finding that another protein linked to AD, tau protein, was seen to decrease with apomorphine treatment. Apomorphine was shown to promote Aβ degradation and inhibit formation through its anti-oxidative properties. Moderate doses were shown to provide the improvements while overuse provided no benefits and may even cause toxicity.

Opioid addiction

In his Deposition: Testimony Concerning a Sickness in the introduction to later editions of Naked Lunch, William S. Burroughs wrote that apomorphine treatment was the only effective cure to opioid addiction he has encountered:

The apomorphine cure is qualitatively different from other methods of cure. I have tried them all. Short reduction, slow reduction, cortisone, antihistamines, tranquilizers, sleeping cures, tolserol, reserpine. None of these cures lasted beyond the first opportunity to relapse. I can say that I was never metabolically cured until I took the apomorphine cure... The doctor, John Yerbury Dent, explained to me that apomorphine acts on the back brain to regulate the metabolism and normalize the blood stream in such a way that the enzyme stream of addiction is destroyed over a period of four to five days. Once the back brain is regulated apomorphine can be discontinued and only used in case of relapse.

He goes on to lament the fact that as of his writing, little to no research has been done on apomorphine or variations of the drug to study its effects on curing addiction, and perhaps the possibility of retaining the positive effects while removing the side effect of vomiting.

Despite his claims throughout his life, Burroughs never really cured his addiction and was back to using opiates within years of his apomorphine "cure". However, he insisted on apomorphine’s effectiveness in several works and interviews.

Pharmacology

Apomorphine possesses affinity for the following receptors:

It has >1,000 nM affinity for 5-HT_1B, 5-HT_1D, and α_1A-adrenergic, and >10,000 nM affinity for β-adrenergic, H₁, and mACh.

Apomorphine behaves as a partial agonist at D_2S (IA = 79%), D_2L (IA= 53%), D₃ (IA = 82%), and D₄ (IA = 45%), and as an antagonist at 5-HT_1B, 5-HT_1D, 5-HT_2A, 5-HT_2B, 5-HT_2C, α₁-adrenergic, and α₂-adrenergic. Though its efficacies at D₁ and D₅ are unclear, it is known to act as an agonist at these sites.

Toxicity

LD₅₀

Properties

Apomorphine is colourless as a liquid but stains green, therefore care must be taken to avoid splashes. Apomorphine does not remain stable for more than 24 hours in a plastic container, so syringes are discarded if not used within 24 hours.

Synthesis

Several techniques exist for the creation of apomorphine from morphine. In the past, morphine has been combined with hydrochloric acid (HCl) at high temperatures, around 150 °C, to achieve a low yield of apomorphine which can range anywhere from 0.6% to 46%.

More recent techniques create the derivative of morphine in a similar fashion, by heating it in the presence of any acid that will promote the essential dehydration rearrangement of morphine type alkaloids, such as phosphoric acid. The method then deviates by including a water scavenger, which is essential to remove the water produced by the reaction that can react with the product and lead to decreased yield. The scavenger can be any reagent that will irreversibly react with water such as phthalic anhydride or titanium chloride. The temperature required for the reaction varies based upon choice of acid and water scavenger. The yield of this reaction is much higher, and is at least 55%.

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