Objective: Characterize the functional activity of apomorphine relative to dopamine using a modern panel of G protein-coupled receptor biosensor assays.

Background: The structural similarity of apomorphine to dopamine was first noted in 1967. Since then, several studies have shown that apomorphine acts as a dopamine agonist activating all dopamine receptor subtypes (D1-D5). However, these assays were performed in disparate systems, often without comparison to dopamine, and did not consider activity on cAMP and β-arrestin signaling cascades.

Method: Functional activity of apomorphine and dopamine was assessed using proprietary cell lines and bioassays performed according to manufacturer protocols (PathHunter® GPCR β-Arrestin assay and Lead Hunter® and Hit Hunter® cAMP assays, Eurofins). The agonist effect of apomorphine at dopamine D1, D2S, D2L, D3, D4, and D5 receptors was calculated as a percentage of the dopamine (i.e., the control) response.

Results: Apomorphine exhibited greater potency (lower EC₅₀ concentrations) than dopamine at most dopamine receptor subtypes, most prominently for D2S, D2L, and D4 receptors when assessing the cAMP pathway [Table 1]. The exception was D3 receptors, where apomorphine was less potent for the cAMP pathway than dopamine. Compared with dopamine, apomorphine engagement of β-arrestin signaling was dampened for D1 (E_max=28%), D4 (E_max=52%), and D5 receptors (E_max=76%) but less so for D2S (E_max=90%), D2L (E_max=83%) and D3 (E_max=94%).

Conclusion: This experiment confirmed, in a series of assays, that apomorphine has affinity to all dopamine receptors, similar to the endogenous neurotransmitter dopamine, but with greater potency. This profile stands in contrast to the dopamine receptor profile seen with other dopamine agonists currently used in Parkinson disease, which demonstrate D2-family predominance. Relative to dopamine, apomorphine exhibits a balanced agonist profile for D2 and D3 receptors in terms of secondary messenger signaling, but for D1, D4, and D5 receptors it displays preferential engagement of G protein signaling.

Table 1

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MDS Abstracts - https://www.mdsabstracts.org/abstract/functional-activity-of-apomorphine-relative-to-dopamine-at-dopamine-receptors-findings-from-g-protein-coupled-receptor-biosensor-assays/