Lal, Samarthji: Apomorphine in the evaluation of dopaminergic function in man. Prog. Neuro-Psychopharmacol. & Biol. Psychiat. 1988, 12 :117–164 1. Apomorphine (Apo), a short acting dopamine (DA) receptor agonist, stimulates growth hormone (GH) secretion, decreases prolactin secretion, induces yawning, penile erections and other physiological effects in man. An effect on behavior, movement disorders and alcoholism has also been described 2. Apo-mediated responses are used to evaluate DA function in psychiatric and neurological disorders. Many of the studies in schizophrenia using the GH response to Apo as an index of central DA function are difficult to interpret because of failure to control for key variables 3. The GH response to Apo is a useful system to evaluate the effects of various drugs including peptides which may not cross the blood brain barrier on DA function in man 4. Apo is a potent sedative. Specific antimanic, antischizophrenic, and anticraving effects in alcoholics have not been convincingly demonstrated. Side effects of Apo and failure to use active placebo make double-blind studies difficult 5. Apo improves parkinsonian symptoms and certain forms of reflex epilepsy but beneficial effects in other involuntary movement disorders requires further documentation 6. Apo may be a useful agent to evaluate DA function in impotent patients and predict a therapeutic response to long-acting dopaminergic agents 7. Impairment of DA function may play a role in diabetic impotence 8. The development of a simple polygraphic method to monitor the yawning response to Apo may facilitate clinical studies on the basic physiology of yawning in man and the use of the yawning response as a measure of central DA function in schizophrenia and other clinical disorders 9. The use of Apo with 18F-fluorodeoxyglucose positron emission tomography to examine regional DA function in man opens up a promising area of research 10. Though long-acting orally active aporphine DA agonists and antagonists have been developed the problem of tolerance may limit their therapeutic potential

Apomorphine in the evaluation of dopaminergic function in man.

Publisher Summary This chapter discusses the chemistry, pharmacology, and the biochemistry of apomorphine Apomorphine (APO) is a tertiary base with the empirical formula C 17 H 17 NO 2  Its molecular skeleton consists of four fused six-membered rings, giving the molecule a semirigid structure Its molecular skeleton is that of an aporphine alkaloid; owing to the catechol moiety in ring D, it oxidizes rapidly and becomes green on exposure to air and in solution APO can be acetylated to diacetylapomorphine without loss of potency However, etherification leads invariably to less active or inactive compounds 11-Hydroxy-10-methoxyaporphine (apocodeine) and 10,11-methylenedioxyaporphine are about four times less potent than APO in inducing stereotyped gnawing in rats, while 10,11 -dimethoxyaporphine is inactive Monohydroxy derivatives of aporphine are inactive The N -methyl group of 10-or 11-hydroxyaporphine is replaced by a N - n -propyl substituent, some activity is retained; these compounds are nevertheless less potent than APO It is concluded that the 10, 11-dihydroxy substitution pattern of APO is an absolute requirement for optimal activity

Apomorphine: chemistry, pharmacology, biochemistry.

Apomorphine in patients with Parkinson's disease

Thebaine (VII) has been degraded to (−)-cis-[2-methyl-2-carboxy-cyclohexyl-(1)]-acetic acid (III), thus providing experimental proof of the absolute configuration of morphine, thebaine and related alkaloids.

Über die absolute Konfiguration des Morphins und verwandter Alkaloide

The present paper consists of a comprehensive review of the literature on apomorphine pharmacological properties and its usefulness in Parkinson’s disease (PD). The chemistry, structure–activity relationship, pharmacokinetics and pharmacodynamics of apomorphine are described with regard to its effects on PD symptoms, drug interactions, interindividual variability and adverse events. Apomorphine chemical structure accounts for most of its beneficial and deleterious properties, both dopaminergic and non-dopaminergic. Its pharmacokinetics and pharmacodynamics are complex and subject to interindividual variability, particularly for subcutaneous absorption and metabolism. Subcutaneous apomorphine, either as injections or infusion, is particularly useful for the treatment of PD motor symptoms and growing evidence supports its clinical value for nonmotor disorders. Owing to interindividual variability and sensitivity, apomorphine treatment must be tailored to each patient. While the subcutaneous route has been the gold standard for decades, the search for alternative routes is ongoing, with promising results from studies of pulmonary, sublingual and transdermal routes. In addition, the potential of apomorphine as a disease-modifying therapy deserves to be investigated, as well as its ability to induce brain plasticity through chronic infusion. Moreover, the ongoing progress in the development of analytical methods should be accompanied by new pharmacokinetic and pharmacodynamic studies of apomorphine metabolism and sites of action in humans, as its biochemistry has yet to be fully described.

B. Jaeckel

Papers

Über die Constitution des Apomorphins