The in vitro receptor profile of rotigotine: a new agent for the treatment of Parkinson’s disease

Abstract

Rotigotine (Neupro) is a non-ergoline dopamine agonist developed for the once daily treatment of Parkinson's disease (PD) using a transdermal delivery system (patch) which provides patients with the drug continuously over 24 h. To fully understand the pharmacological actions of rotigotine, the present study determined its extended receptor profile. In standard binding assays, rotigotine demonstrated the highest affinity for dopamine receptors, particularly the dopamine D3 receptor (Ki=0.71 nM) with its affinities to other dopamine receptors being (Ki in nM): D4.2 (3.9), D4.7 (5.9), D5 (5.4), D2 (13.5), D4.4 (15), and D1 (83). Significant affinities were also demonstrated at alpha-adrenergic (alpha2B, Ki=27 nM) and serotonin receptors (5-HT1A Ki=30 nM). In newly developed reporter-gene assays for determination of functional activity, rotigotine behaved as a full agonist at dopamine receptors (rank order: D3>D2L>D1=D5>D4.4) with potencies 2,600 and 53 times higher than dopamine at dopamine D3 and D2L receptors, respectively. At alpha-adrenergic sites, rotigotine acted as an antagonist on alpha2B receptors. At serotonergic sites, rotigotine had a weak but significant agonistic activity at 5-HT1A receptors and a minor or nonexistent activity at other serotonin receptors. Thus, in respect to PD, rotigotine can be characterized as a specific dopamine receptor agonist with a preference for the D3 receptor over D2 and D1 receptors. In addition, it exhibits interaction with D4 and D5 receptors, the role of which in relation to PD is not clear yet. Among non-dopaminergic sites, rotigotine shows relevant affinity to only 5-HT1A and alpha2B receptors. Further studies are necessary to investigate the contribution of the different receptor subtypes to the efficacy of rotigotine in Parkinson's disease and possible other indications such as restless legs syndrome.

Possible Treatments of Atypical Parkinsonism

“…Finally, during the study the patients did not suffer from congestive heart failure. These results confirm previous evidences obtained in patients with idiopathic Parkinson's disease showing positive effect on motor control and behavioral disturbances [47][48][49][50][51][52][53][54][55] as well as a good safety of RTG [56]. On the whole, these outcomes highlight that transdermal RTG should be considered as a therapeutic option for the treatment of atypical parkinsonism.…”

Upregulation of D2-class signaling in dopamine-denervated striatum is in part mediated by D3receptors acting on CaV2.1 channels via PIP2depletion

“…To conclude, when in vitro and in vivo data are taken together, they suggest that a control of D 3 R supersensitivity is essential for improving L-DOPA actions, movement performance, and the control of dyskinesias, as has been observed by employing more selective D 3 R partial agonists (e.g., rotigotine and pramipexole) (Scheller et al 2009). By contrast, D 3 R antagonists worsen both Parkinsonian and dyskinetic states (Bezard et al 2003).…”

Impact of 6-month earlier versus postponed initiation of rotigotine on long-term outcome:post hocanalysis of patients with early Parkinson’s disease with mild symptom severity

“…Rotigotine is a non-ergoline dopamine receptor agonist (DA) with activity across D1 through D5 receptors as well as select adrenergic and serotonergic sites [13]. It is applied once daily using a transdermal patch, enabling continuous drug delivery and stable plasma levels over a 24-h period [14].…”