Receptor-binding and pharmacokinetic properties of dopaminergic agonists.

Article Details

Citation

Kvernmo T, Houben J, Sylte I

Receptor-binding and pharmacokinetic properties of dopaminergic agonists.

Curr Top Med Chem. 2008;8(12):1049-67.

PubMed ID
18691132 [ View in PubMed
]
Abstract

This review describes symptoms and pathophysiology of Parkinson's diseases (PD) and restless legs syndrome (RLS), and discusses the relationship between clinical outcome of DA agonists and their receptor-binding and pharmacokinetics. Oral DA agonists are divided into 2 classes; the ergots and the non-ergots. Both classes are in general equally effective against PD motor symptoms. Ergots (apart from bromocriptine) stimulate the DA D(1) subreceptor and increase dyskinesia. Furthermore, valvular heart disease (VHD) and pulmonary and retroperitoneal fibrosis appear to represent a class effect of 8beta-aminoergolines as cabergoline and pergolide The side effects profile therefore seems more beneficial for non-ergots than ergots. The main improvement of motor functions by DA agonists is related to D(2) agonism. However, in monotheraphy, the selective D(2)-receptor DA agonist sumanirole seemed less effective than ropinirole which is selective for D(2)-like DA-receptors (D(2), D(3) and D(4)). Given as adjunctive to L-dopa both drugs had equal efficacy on motor-symptoms, indicating that D(2)-receptor activity must be accompanied with stimulation of other DA receptors for optimizing the efficacy on motor symptoms. Striatal D(3) receptor loss may be more important than D(2) receptor loss for reduced response to dopaminergic treatment. D(3) stimulation may also be beneficial for the non-motor symptom depression/mood in PD and for neuron-protection. This makes D(3)-receptors a potential therapeutic target in PD. 5-HT(1A)-receptor agonism and alpha(2) adrenergic antagonism may contribute to prevention of dyskinesia. However, 5-HT-receptor activity is also associated with side effects. 5-HT(2B) agonism (and possibly 5-HT(1B) agonism) is associated with fibrotic reactions, and valvular heart disease (VHD). By interfering with the CYP450 system DA agonists may contribute to drug-drug interactions. Lack of CYP2D6 activity is also suggested as important for etiology and CNS-symptoms of PD. Based on current knowledge D2-like receptor activities (preferences for the D(3) receptor) seem most beneficial. 5-HT(1A)-receptor agonism (prevention of dyskinesia), 5-HT(2B) antagonism or no 5-HT(2B)-receptor activity also seems beneficial. Development of DA agonists containing these properties, without interfering with CYP2D6 may be beneficial.

DrugBank Data that Cites this Article

Drugs
Drug Targets
DrugTargetKindOrganismPharmacological ActionActions
Apomorphine5-hydroxytryptamine receptor 1AProteinHumans
Unknown
Agonist
Details
Apomorphine5-hydroxytryptamine receptor 1BProteinHumans
Unknown
Agonist
Details
Apomorphine5-hydroxytryptamine receptor 1DProteinHumans
Unknown
Agonist
Details
Apomorphine5-hydroxytryptamine receptor 2AProteinHumans
Unknown
Agonist
Details
Apomorphine5-hydroxytryptamine receptor 2BProteinHumans
Unknown
Agonist
Details
Apomorphine5-hydroxytryptamine receptor 2CProteinHumans
Unknown
Agonist
Details
ApomorphineAlpha-2A adrenergic receptorProteinHumans
Unknown
Agonist
Details
ApomorphineAlpha-2B adrenergic receptorProteinHumans
Unknown
Agonist
Details
ApomorphineAlpha-2C adrenergic receptorProteinHumans
Unknown
Agonist
Details
ApomorphineD(1A) dopamine receptorProteinHumans
Unknown
Agonist
Details
ApomorphineD(1B) dopamine receptorProteinHumans
Unknown
Agonist
Details
ApomorphineD(2) dopamine receptorProteinHumans
Yes
Agonist
Details
ApomorphineD(4) dopamine receptorProteinHumans
Yes
Agonist
Details
Bromocriptine5-hydroxytryptamine receptor 1AProteinHumans
Unknown
Agonist
Details
Bromocriptine5-hydroxytryptamine receptor 1BProteinHumans
Unknown
Agonist
Details
Bromocriptine5-hydroxytryptamine receptor 1DProteinHumans
Unknown
Agonist
Details
Bromocriptine5-hydroxytryptamine receptor 2AProteinHumans
Unknown
Agonist
Details
Bromocriptine5-hydroxytryptamine receptor 2BProteinHumans
Unknown
Agonist
Details
Bromocriptine5-hydroxytryptamine receptor 2CProteinHumans
Unknown
Agonist
Details
BromocriptineAlpha-2A adrenergic receptorProteinHumans
Unknown
Agonist
Details
BromocriptineAlpha-2B adrenergic receptorProteinHumans
Unknown
Agonist
Details
BromocriptineAlpha-2C adrenergic receptorProteinHumans
Unknown
Agonist
Details
BromocriptineD(1A) dopamine receptorProteinHumans
Unknown
Agonist
Details
BromocriptineD(1B) dopamine receptorProteinHumans
Unknown
Agonist
Details
BromocriptineD(2) dopamine receptorProteinHumans
Yes
Agonist
Details
BromocriptineD(3) dopamine receptorProteinHumans
Yes
Agonist
Details
BromocriptineD(4) dopamine receptorProteinHumans
Unknown
Antagonist
Details
Cabergoline5-hydroxytryptamine receptor 1AProteinHumans
Unknown
Agonist
Details
Cabergoline5-hydroxytryptamine receptor 1BProteinHumans
Unknown
Agonist
Details
Cabergoline5-hydroxytryptamine receptor 1DProteinHumans
Unknown
Agonist
Details
Cabergoline5-hydroxytryptamine receptor 2AProteinHumans
Unknown
Agonist
Details
Cabergoline5-hydroxytryptamine receptor 2BProteinHumans
Unknown
Agonist
Details
Cabergoline5-hydroxytryptamine receptor 2CProteinHumans
Unknown
Agonist
Details
CabergolineAlpha-2A adrenergic receptorProteinHumans
Unknown
Antagonist
Details
CabergolineAlpha-2B adrenergic receptorProteinHumans
Unknown
Antagonist
Details
CabergolineAlpha-2C adrenergic receptorProteinHumans
Unknown
Antagonist
Details
CabergolineD(1A) dopamine receptorProteinHumans
Unknown
Agonist
Details
CabergolineD(1B) dopamine receptorProteinHumans
Unknown
Agonist
Details
CabergolineD(3) dopamine receptorProteinHumans
Unknown
Agonist
Details
CabergolineD(4) dopamine receptorProteinHumans
Unknown
Agonist
Details
Lisuride5-hydroxytryptamine receptor 1AProteinHumans
Unknown
Agonist
Details
Lisuride5-hydroxytryptamine receptor 1BProteinHumans
Unknown
Agonist
Details
Lisuride5-hydroxytryptamine receptor 1DProteinHumans
Unknown
Agonist
Details
Lisuride5-hydroxytryptamine receptor 2AProteinHumans
Yes
Agonist
Details
Lisuride5-hydroxytryptamine receptor 2BProteinHumans
Unknown
Antagonist
Details
Lisuride5-hydroxytryptamine receptor 2CProteinHumans
Yes
Agonist
Details
LisurideAlpha-2A adrenergic receptorProteinHumans
Unknown
Other/unknown
Details
LisurideAlpha-2B adrenergic receptorProteinHumans
Unknown
Other/unknown
Details
LisurideAlpha-2C adrenergic receptorProteinHumans
Unknown
Other/unknown
Details
LisurideD(1A) dopamine receptorProteinHumans
Unknown
Antagonist
Details
LisurideD(1B) dopamine receptorProteinHumans
Unknown
Antagonist
Details
LisurideD(2) dopamine receptorProteinHumans
Yes
Agonist
Details
LisurideD(3) dopamine receptorProteinHumans
Yes
Agonist
Details
LisurideD(4) dopamine receptorProteinHumans
Yes
Agonist
Details
Pergolide5-hydroxytryptamine receptor 1AProteinHumans
Unknown
Agonist
Details
Pergolide5-hydroxytryptamine receptor 1BProteinHumans
Unknown
Agonist
Details
Pergolide5-hydroxytryptamine receptor 1DProteinHumans
Unknown
Agonist
Details
Pergolide5-hydroxytryptamine receptor 2AProteinHumans
Unknown
Agonist
Details
Pergolide5-hydroxytryptamine receptor 2BProteinHumans
Unknown
Agonist
Details
Pergolide5-hydroxytryptamine receptor 2CProteinHumans
Unknown
Agonist
Details
PergolideAlpha-2 adrenergic receptors (Protein Group)Protein groupHumans
Unknown
Agonist
Details
PergolideD(1A) dopamine receptorProteinHumans
Yes
Agonist
Details
PergolideD(1B) dopamine receptorProteinHumans
Yes
Agonist
Details
PergolideD(2) dopamine receptorProteinHumans
Yes
Agonist
Details
PergolideD(3) dopamine receptorProteinHumans
Yes
Agonist
Details
PergolideD(4) dopamine receptorProteinHumans
Yes
Agonist
Details
PramipexoleAlpha-2A adrenergic receptorProteinHumans
Unknown
Agonist
Details
RopiniroleAlpha adrenergic receptor (Protein Group)Protein groupHumans
Unknown
Antagonist
Details
RopiniroleD(2) dopamine receptorProteinHumans
Yes
Agonist
Details
RopiniroleD(3) dopamine receptorProteinHumans
Yes
Agonist
Details
RopiniroleD(4) dopamine receptorProteinHumans
Unknown
Agonist
Details
Rotigotine5-hydroxytryptamine receptor 1AProteinHumans
Unknown
Agonist
Details
RotigotineD(1A) dopamine receptorProteinHumans
Unknown
Agonist
Details
RotigotineD(1B) dopamine receptorProteinHumans
Unknown
Agonist
Details
RotigotineD(2) dopamine receptorProteinHumans
Yes
Agonist
Details
RotigotineD(3) dopamine receptorProteinHumans
Yes
Agonist
Details
RotigotineD(4) dopamine receptorProteinHumans
Yes
Agonist
Details
Drug Enzymes
DrugEnzymeKindOrganismPharmacological ActionActions
BromocriptineCytochrome P450 3A4ProteinHumans
No
Substrate
Inhibitor
Details
CabergolineCytochrome P450 3A4ProteinHumans
Unknown
Substrate
Details
LisurideCytochrome P450 3A4ProteinHumans
Unknown
Substrate
Details
RopiniroleCytochrome P450 1A2ProteinHumans
Unknown
Substrate
Details
RotigotineCytochrome P450 2D6ProteinHumans
Unknown
Substrate
Inhibitor
Details
RotigotineCytochrome P450 3A4ProteinHumans
Unknown
Substrate
Details