Apomorphine dopamine antagonist

Metoclopramide, administered at doses higher than those required to inhibit apomorphine-induced emesis, was more effective than haloperidol in antagonizing cisplatin-induced emesis in dogs [80]. This was observed despite the fact that metoclopramide was considerably weaker than haloperidol as a D2-dopamine antagonist [43]. Subsequently, antiemetic efficacy of metoclopramide administered at high doses has been reported in cancer patients... 

The synthesis of a number of radiolabelled apomorphine derivatives has been described.59-62 A full paper has appeared on the preparation of (—)-2,10,11-trihydroxy-/V-(n-propyl)noraporphine, a dopaminergic compound with anticonvulsant activity.63 The potential dopamine-inhibiting properties of (—)-N-(2-chloroethyl)norapomorphine and related compounds have been assessed. A-Chloroethylation in the aporphine series can abolish dopamine agonist action, and can confer a long-lasting dopamine antagonist potential.64... 

Apomorphine, a dopamine antagonist, is given by subcutaneous injection. Nausea can occur. 

Note that prochlorperazine should not be given if apomorphine is used for Parkinson s disease, as its dopamine antagonist actions can worsen the disease (see also Levodopa + Antiemetics , p.682). Because apomorphine is highly emetogenic at the doses required for the treatment of Parkinson s disease (1 to 4 mg/hour by subcutaneous infusion), patients with Parkinson s disease requiring apomorphine should be pretreated with domperidone 20 mg three times daily for at least 2 days. Rare reports of extrapyramidal adverse effects have been reported with ondansetron, which may be of relevance in patients with Parkinson s Disease. 

Apomorphine is approved for acute off episodes in patients with advanced stages of PD. The onset of effect is within 10 to 20 minutes and the duration of effect is about 60 minutes. It requires premedication with an antiemetic because it causes nausea and vomiting. Antiemetics that block central dopamine worsen the symptoms of PD, and 5-HT3 antagonists, such as ondansetron, can aggravate PD-related hypotension. Trimethobenzamide (300 mg three times daily) should be... 

Domperidone [133], one of the most potent D2-dopamine blockers and antagonists of apomorphine-induced emesis with limited brain-blood barrier permeability, did not establish a position as an antiemetic, especially against cisplatin [134], Recently, the use of domperidone as a parenteral antiemetic has been discontinued because of serious cardiovascular toxicity. 

Dopamine - low doses of the dopamine agonist apomorphine increase slow-wave sleep and, like other dopaminometics, cause somnolence in patients with Parkinson s disease. Conversely, dopamine autoreceptor antagonists, which enhance dopamine release, reduce both REM and non-REM sleep. Stimulants such as cocaine cause arousal by activating D2 postsynaptic receptors, effects which are blocked by most neuroleptics. 

In either the presence or absence of GTP, half-maximal stimulation of enzyme activity is achieved with 3 uM dopamine. Both 6,7-ADTM and epinine (K-methyl dopamine) stimulate adenylate cyclase activity to the same degree as does dopamine (Figure 8). In contrast, apomorphine is a partial agonist eliciting only 30 of the maximal effect of dopamine. The dopamine-stimulated adenylate cyclase activity is selectively blocked by cis-flupenthixol rather than the trans-isomer of this antagonist (JJL). Among the antagonists tested, the order of potency is cis-flupenthixol = fluphenazine > chlorpromazine > haloperidol > trans-flupenthixol (Table I). 

In fact the most important point concerns the very poor pharmacological characterization of the cAMP formation enhanced by dopamine and of the parathormone secretion. Firstly, apomorphine is much less potent than dopamine, a fact which is not compatible with what we know from pharmacological, behavioural and even biochemical studies (3,4 7) It is believed that apomorphine is a partial antagonist, but this has never been found in in vivo conditions. The higher potency of apomorphine is also reflected by its high affinity in %-haloperidol and 3H-spiperone binding. 

More recently, we initiated a series of experiments to test the activity of new derivatives of apomorphine, some of which had been classified as dopamine agonists or antagonists (40-45). Pretreatment of rats with 50 or 100 ug/100 g body weight of (-)N-n-propylnorapomorphine (NPA) or the prodrug (-)... 

Mansbach RS, Brooks EW, Sanner MA, Zorn SH (1998) Selective dopamine D4 receptor antagonists reverse apomorphine-induced blockade of prepulse inhibition. Psychopharmacol 735 194-200. 

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