Apomorphine
Encyclopedia
Apomorphine is a non-selective
dopamine agonist
which activates both D1-like
and D2-like receptor
s, 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 receptor
s 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.
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 dyskinesia
s 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.
(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.
.
, 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.
s:
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.
and concentrated hydrochloric acid
at 140ºC.
Binding selectivity
Binding selectivity refers to the differing affinities with which different ligands bind to a substrate forming a complex. A selectivity coefficient is the equilibrium constant for the reaction of displacement by one ligand of another ligand in a complex with the substrate...
dopamine agonist
Dopamine agonist
A dopamine agonist is a compound that activates dopamine receptors in the absence of dopamine. Dopamine agonists activate signaling pathways through the dopamine receptor and trimeric G-proteins, ultimately leading to changes in gene transcription.-Uses:...
which activates both D1-like
D1-like receptor
The D1-like receptors are a subfamily of dopamine receptors that bind the endogenous neurotransmitter dopamine. The D1-like subfamily consists of two G-protein coupled receptors which are coupled to Gs and mediate excitatory neurotransmission, including D1 and D5. For more information, please see...
and D2-like receptor
D2-like receptor
The D2-like receptors are a subfamily of dopamine receptors that bind the endogenous neurotransmitter dopamine. The D2-like subfamily consists of three G-protein coupled receptors which are coupled to Gi/Go and mediate inhibitory neurotransmission, including D2, D3, and D4...
s, with some preference for the latter subtypes. It is historically a morphine
Morphine
Morphine is a potent opiate analgesic medication and is considered to be the prototypical opioid. It was first isolated in 1804 by Friedrich Sertürner, first distributed by same in 1817, and first commercially sold by Merck in 1827, which at the time was a single small chemists' shop. It was more...
decomposition product by boiling with concentrated acid, hence the -morphine suffix. Apomorphine does not actually contain morphine or its skeleton, or bind to opioid receptor
Opioid receptor
Opioid receptors are a group of G protein-coupled receptors with opioids as ligands. The endogenous opioids are dynorphins, enkephalins, endorphins, endomorphins and nociceptin. The opioid receptors are ~40% identical to somatostatin receptors...
s for that matter. The apo- prefix relates to it being an aporphine
Aporphine
Aporphine is one of a class of quinoline alkaloids. Many different relatives of this compound have been purified from plants.One commonly-used aporphine derivative is apomorphine....
derivative.
Historically, apomorphine has been tried for a variety of uses including psychiatric "treatment" of homosexuality
Sexual orientation and medicine
Sexual orientation and medicine may refer to:*Medical association positions and policy regarding sexual orientation or homosexuality*Timeline of sexual orientation and medicine*Homosexuality and psychology...
in the early 20th century, and more recently in treating erectile dysfunction
Erectile dysfunction
Erectile dysfunction is sexual dysfunction characterized by the inability to develop or maintain an erection of the penis during sexual performance....
. Currently, apomorphine is used in the treatment of Parkinson's disease
Parkinson's disease
Parkinson's disease is a degenerative disorder of the central nervous system...
. It is a potent emetic (i.e., it induces vomiting) and should not be administered without an antiemetic
Antiemetic
An antiemetic is a drug that is effective against vomiting and nausea. Antiemetics are typically used to treat motion sickness and the side effects of opioid analgesics, general anaesthetics, and chemotherapy directed against cancer....
such as domperidone
Domperidone
Domperidone is an antidopaminergic drug, developed by Janssen Pharmaceutica, and used orally, rectally or intravenously, generally to suppress nausea and vomiting, or as a prokinetic agent...
. 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
William S. Burroughs
William Seward Burroughs II was an American novelist, poet, essayist and spoken word performer. A primary figure of the Beat Generation and a major postmodernist author, he is considered to be "one of the most politically trenchant, culturally influential, and innovative artists of the 20th...
. A recent study indicates that apomorphine might be a suitable marker for assessing central dopamine
Dopamine
Dopamine is a catecholamine neurotransmitter present in a wide variety of animals, including both vertebrates and invertebrates. In the brain, this substituted phenethylamine functions as a neurotransmitter, activating the five known types of dopamine receptors—D1, D2, D3, D4, and D5—and their...
system alterations associated with chronic heroin consumption. There is, however, no clinical evidence that apomorphine is an effective and safe treatment regimen for opiate
Opiate
In medicine, the term opiate describes any of the narcotic opioid alkaloids found as natural products in the opium poppy plant.-Overview:Opiates are so named because they are constituents or derivatives of constituents found in opium, which is processed from the latex sap of the opium poppy,...
addiction
Addiction
Historically, addiction has been defined as physical and psychological dependence on psychoactive substances which cross the blood-brain barrier once ingested, temporarily altering the chemical milieu of the brain.Addiction can also be viewed as a continued involvement with a substance or activity...
. Early studies involved aversion therapy
Aversion therapy
Aversion therapy is a form of psychological treatment in which the patient is exposed to a stimulus while simultaneously being subjected to some form of discomfort...
in alcoholism
Alcoholism
Alcoholism is a broad term for problems with alcohol, and is generally used to mean compulsive and uncontrolled consumption of alcoholic beverages, usually to the detriment of the drinker's health, personal relationships, and social standing...
and anxiety
Anxiety
Anxiety is a psychological and physiological state characterized by somatic, emotional, cognitive, and behavioral components. The root meaning of the word anxiety is 'to vex or trouble'; in either presence or absence of psychological stress, anxiety can create feelings of fear, worry, uneasiness,...
, and modern reports are rather anecdotal.
For treatment of erectile dysfunction, it is believed that dopamine receptors in the hypothalamic region of the brain
Brain
The brain is the center of the nervous system in all vertebrate and most invertebrate animals—only a few primitive invertebrates such as sponges, jellyfish, sea squirts and starfishes do not have one. It is located in the head, usually close to primary sensory apparatus such as vision, hearing,...
are the main target, as although dopamine receptors in the penis
Penis
The penis is a biological feature of male animals including both vertebrates and invertebrates...
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 antiemeticAntiemetic
An antiemetic is a drug that is effective against vomiting and nausea. Antiemetics are typically used to treat motion sickness and the side effects of opioid analgesics, general anaesthetics, and chemotherapy directed against cancer....
domperidone
Domperidone
Domperidone is an antidopaminergic drug, developed by Janssen Pharmaceutica, and used orally, rectally or intravenously, generally to suppress nausea and vomiting, or as a prokinetic agent...
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 dyskinesia
Dyskinesia
Dyskinesia is a movement disorder which consists of effects including diminished voluntary movements and the presence of involuntary movements, similar to tics or choreia. Dyskinesia can be anything from a slight tremor of the hands to uncontrollable movement of, most commonly, the upper body but...
s 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 dysfunctionErectile dysfunction
Erectile dysfunction is sexual dysfunction characterized by the inability to develop or maintain an erection of the penis during sexual performance....
(male impotence). It is its mode of stimulating dopamine
Dopamine
Dopamine is a catecholamine neurotransmitter present in a wide variety of animals, including both vertebrates and invertebrates. In the brain, this substituted phenethylamine functions as a neurotransmitter, activating the five known types of dopamine receptors—D1, D2, D3, D4, and D5—and their...
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
University of Portsmouth
The University of Portsmouth is a university in Portsmouth, Hampshire, England. The University was ranked 60th out of 122 in The Sunday Times University Guide...
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 diseaseAlzheimer's disease
Alzheimer's disease also known in medical literature as Alzheimer disease is the most common form of dementia. There is no cure for the disease, which worsens as it progresses, and eventually leads to death...
.
Opiate addiction
In his Deposition: Testimony Concerning a Sickness in the introduction to later editions of Naked LunchNaked Lunch
Naked Lunch is a novel by William S. Burroughs originally published in 1959. The book is structured as a series of loosely-connected vignettes. Burroughs stated that the chapters are intended to be read in any order...
, William S. Burroughs
William S. Burroughs
William Seward Burroughs II was an American novelist, poet, essayist and spoken word performer. A primary figure of the Beat Generation and a major postmodernist author, he is considered to be "one of the most politically trenchant, culturally influential, and innovative artists of the 20th...
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
Cortisone
Cortisone is a steroid hormone. It is one of the main hormones released by the adrenal gland in response to stress. In chemical structure, it is a corticosteroid closely related to corticosterone. It is used to treat a variety of ailments and can be administered intravenously, orally,...
, antihistamines, tranquilizers, sleeping cures, tolserol, reserpine
Reserpine
Reserpine is an indole alkaloid antipsychotic and antihypertensive drug that has been used for the control of high blood pressure and for the relief of psychotic symptoms, although because of the development of better drugs for these purposes and because of its numerous side-effects, it is rarely...
. 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 receptorReceptor (biochemistry)
In biochemistry, a receptor is a molecule found on the surface of a cell, which receives specific chemical signals from neighbouring cells or the wider environment within an organism...
s:
- 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-HT1A5-HT1A receptorThe 5-HT1A receptor is a subtype of 5-HT receptor that binds the endogenous neurotransmitter serotonin . It is a G protein-coupled receptor that is coupled to Gi/Go and mediates inhibitory neurotransmission...
(Ki = 117 nM) - 5-HT2A5-HT2A receptorThe mammalian 5-HT2A receptor is a subtype of the 5-HT2 receptor that belongs to the serotonin receptor family and is a G protein-coupled receptor . This is the main excitatory receptor subtype among the GPCRs for serotonin , although 5-HT2A may also have an inhibitory effect on certain areas such...
(Ki = 120 nM) - 5-HT2B5-HT2B receptor5-hydroxytryptamine receptor 2B, also known as HTR2B, is a 5-HT2 receptor, but also denotes the human gene encoding it.-Function:...
(Ki = 132 nM) - 5-HT2C5-HT2C receptorThe 5-HT2C receptor is a subtype of 5-HT receptor that binds the endogenous neurotransmitter serotonin . It is a G protein-coupled receptor that is coupled to Gq/G11 and mediates excitatory neurotransmission. HTR2C denotes the human gene encoding for the receptor, that in humans is located at the...
(Ki = 102 nM)
- α1B-adrenergicAlpha-1B adrenergic receptorThe alpha-1B adrenergic receptor , also known as ADRA1B, is an alpha-1 adrenergic receptor, and also denotes the human gene encoding it.-Interactions:...
(Ki = 676 nM) - α1D-adrenergicAlpha-1D adrenergic receptorThe alpha-1D adrenergic receptor , also known as ADRA1D, is an alpha-1 adrenergic receptor, and also denotes the human gene encoding it.-Further reading:...
(Ki = 65 nM) - α2A-adrenergicAlpha-2A adrenergic receptorThe alpha-2A adrenergic receptor , also known as ADRA2A, is an alpha-2 adrenergic receptor, and also denotes the human gene encoding it.-Role in Central Nervous System:...
(Ki = 141 nM) - α2B-adrenergicAlpha-2B adrenergic receptorThe alpha-2B adrenergic receptor , is a G-protein coupled receptor. It is a subtype of the adrenergic receptor family. The human gene encoding this receptor has the symbol ADRA2B.ADRA2B orthologs have been identified in several mammals....
(Ki = 66 nM) - α2C-adrenergicAlpha-2C adrenergic receptorThe alpha-2C adrenergic receptor , also known as ADRA2C, is an alpha-2 adrenergic receptor, and also denotes the human gene encoding it.-Agonists:* -3-Nitrobiphenyline -Antagonists:...
(Ki = 36 nM)
It has > 1,000 nM affinity for 5-HT1B, 5-HT1D, and α1A-adrenergic
Alpha-1A adrenergic receptor
The alpha-1A adrenergic receptor , also known as ADRA1A, formerly known as the alpha-1C adrenergic receptor, is an alpha-1 adrenergic receptor, and also denotes the human gene encoding it.-Agonists:...
, and > 10,000 nM affinity for β-adrenergic, H1
H1 receptor
The H1 receptor is a histamine receptor belonging to the family of Rhodopsin like G-protein-coupled receptors. This receptor, which is activated by the biogenic amine histamine, is expressed throughout the body, to be specific, in smooth muscles, on vascular endothelial cells, in the heart, and in...
, and mACh
Muscarinic acetylcholine receptor
Muscarinic receptors, or mAChRs, are acetylcholine receptors that form G protein-coupled in the plasma membranes of certain neurons and other cells...
.
Apomorphine behaves as a partial agonist
Partial agonist
Partial agonists bind and activate a given receptor, but have only partial efficacy at the receptor relative to a full agonist...
at D2S ( IA
Intrinsic activity
Intrinsic activity or efficacy refers to the relative ability of a drug-receptor complex to produce a maximum functional response. This must be distinguished from the affinity, which is a measure of the ability of the drug to bind to its molecular target, and the EC50, which is a measure of the...
= 79%), D2L (IA= 53%), D3 (IA = 82%), and D4 (IA = 45%), and as an antagonist
Receptor antagonist
A receptor antagonist is a type of receptor ligand or drug that does not provoke a biological response itself upon binding to a receptor, but blocks or dampens agonist-mediated responses...
at 5-HT1B, 5-HT1D, 5-HT2A, 5-HT2B, 5-HT2C, α1-adrenergic, and α2-adrenergic. Though its efficacies
Intrinsic activity
Intrinsic activity or efficacy refers to the relative ability of a drug-receptor complex to produce a maximum functional response. This must be distinguished from the affinity, which is a measure of the ability of the drug to bind to its molecular target, and the EC50, which is a measure of the...
at D1 and D5 are unclear, it is known to act as an agonist
Agonist
An agonist is a chemical that binds to a receptor of a cell and triggers a response by that cell. Agonists often mimic the action of a naturally occurring substance...
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 morphineMorphine
Morphine is a potent opiate analgesic medication and is considered to be the prototypical opioid. It was first isolated in 1804 by Friedrich Sertürner, first distributed by same in 1817, and first commercially sold by Merck in 1827, which at the time was a single small chemists' shop. It was more...
and concentrated hydrochloric acid
Hydrochloric acid
Hydrochloric acid is a solution of hydrogen chloride in water, that is a highly corrosive, strong mineral acid with many industrial uses. It is found naturally in gastric acid....
at 140ºC.
External links
- PDSP Ki database - Detailed usage guide for Apomorphine pumps for Parkinson's