Apomorphine

Apomorphine (Apokyn, Ixense, Spontane, Uprima) is a non-selective dopamine agonist which activates both D1-like and D2-like receptors, with some preference for the latter subtypes. It is historically a morphine decomposition product by boiling with concentrated acid, hence the -morphine suffix. Apomorphine does not actually contain morphine or its skeleton, or bind to opioid receptors for that matter. The apo- prefix relates to it being an aporphine derivative.

Historically, apomorphine has been tried for a variety of uses including psychiatric "treatment" of homosexuality in the early 20th century, and more recently in treating erectile dysfunction. Currently, apomorphine is used in the treatment of Parkinson's disease. It is a potent emetic (i.e. it induces vomiting) and should not be administered without an antiemetic such as domperidone. The emetic properties of apomorphine are exploited in veterinary medicine to induce therapeutic emesis in canines that have recently ingested toxic or foreign substances.

It was also successfully used as an unofficial treatment of heroin addiction, a purpose for which it was championed by the author William S. Burroughs. A recent study indicates that apomorphine might be a suitable marker for assessing central dopamine system alterations associated with chronic heroin consumption. There is, however, no clinical evidence that apomorphine is an effective and safe treatment regimen for opiate addiction. Early studies involved aversion therapy in alcoholism and anxiety, and modern reports are rather anecdotal.

For treatment of erectile dysfunction, it is believed that dopamine receptors in the hypothalamic region of the brain are the main target, as although dopamine receptors in the penis do facilitate erection, they do so far more weakly than those in the brain.

Alcoholism
Apomorphine was used with some notable success as a treatment for alcohol and morphine addiction. Its chief practitioner in the 1950s was Dr John Yerbury Dent 1888-1961 who, early on in his research, mistakenly believed that it was the emetic properties of apomorphine which was efficacious.

Parkinson's disease
First mooted 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.

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 (avg age 61) discontinuing in month 1 and a further 23% in month 2. UK studies concentrated on males with generalized erectile dysfunction. Uprima effects desire and is not meant to produce an overall effect as say Viagra which works on blood flow. In those males who have problems with desire as opposed to generalized erectile dysfunction it works as expected.

Alzheimer's disease
Apomorphine has been reported to be an inhibitor of Beta amyloid fibril formation, and may thus have potential as a therapeutic for Alzheimer's disease.

Opiate 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 opiate 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 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.  (No one would take apomorphine for kicks.  Not one case of addiction to apomorphine has ever been recorded.)"  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.

Pharmacology
Apomorphine possesses affinity for the following receptors:


 * D1 (Ki = 372 nM)
 * D2S (Ki = 35 nM)
 * D2L (Ki = 83 nM)
 * D3 (Ki = 26 nM)
 * D4 (Ki = 4.4 nM)
 * D5 (Ki = 15 nM)


 * 5-HT1A (Ki = 117 nM)
 * 5-HT2A (Ki = 120 nM)
 * 5-HT2B (Ki = 132 nM)
 * 5-HT2C (Ki = 102 nM)


 * α1B-adrenergic (Ki = 676 nM)
 * α1D-adrenergic (Ki = 65 nM)
 * α2A-adrenergic (Ki = 141 nM)
 * α2B-adrenergic (Ki = 66 nM)
 * α2C-adrenergic (Ki = 36 nM)

It has > 1,000 nM affinity for 5-HT1B, 5-HT1D, and α1A-adrenergic, and > 10,000 nM affinity for β-adrenergic, H1, and mACh.

Apomorphine behaves as a partial agonist at D2S ( IA = 79%), D2L (IA= 53%), D3 (IA  = 82%), and D4 (IA = 45%), and as an antagonist at 5-HT1B, 5-HT1D, 5-HT2A, 5-HT2B, 5-HT2C, 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.

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

Synthesis
Apomorphine hydrochloride is synthesized by heating stoichiometric amounts of morphine and concentrated hydrochloric acid at 140ºC.