Abstract
A series of new aporphine analogues (aporlogues) were synthesized bearing a C-, N-, or O-linkage at the C11 position. Lipoic ester (-)-15 was identified as a full agonist at the dopamine D(2) and serotonin 5-HT(1A) receptors with K(i) values of 174 and 66 nM, respectively. It elicited antiparkinsonian action on Parkinsin's disease (PD) rats with minor dyskinesia. Chronic use of (-)-15 reduced L-DOPA-induced dyskinesia (LID) without attenuating the antiparkinsonian effect. These results suggest that 5-HT(1A) and D(2) dual-receptor agonist (-)-15 may present a novel candidate drug in the treatment of PD and LID.
Publication types
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Research Support, Non-U.S. Gov't
MeSH terms
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Animals
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Antiparkinson Agents / chemical synthesis*
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Antiparkinson Agents / chemistry
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Antiparkinson Agents / pharmacology
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Aporphines / chemical synthesis*
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Aporphines / chemistry
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Aporphines / pharmacology
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Binding, Competitive
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CHO Cells
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Corpus Striatum / metabolism
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Cricetinae
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Cricetulus
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Dyskinesia, Drug-Induced / drug therapy
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Dyskinesia, Drug-Induced / etiology
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HEK293 Cells
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Humans
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Levodopa / adverse effects
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Oxidopamine
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Parkinson Disease / drug therapy*
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Parkinson Disease / etiology
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Proto-Oncogene Proteins c-fos / biosynthesis
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Radioligand Assay
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Rats
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Receptors, Adrenergic / metabolism
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Receptors, Dopamine D2 / agonists*
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Serotonin 5-HT1 Receptor Agonists / chemical synthesis*
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Serotonin 5-HT1 Receptor Agonists / chemistry
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Serotonin 5-HT1 Receptor Agonists / pharmacology
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Stereoisomerism
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Structure-Activity Relationship
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Thioctic Acid / analogs & derivatives*
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Thioctic Acid / chemical synthesis
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Thioctic Acid / chemistry
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Thioctic Acid / pharmacology
Substances
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Antiparkinson Agents
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Aporphines
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Fosb protein, rat
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N-propylnoraporphin-11-yl 5-(1,2-dithiolan-3-yl)pentanoate
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Proto-Oncogene Proteins c-fos
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Receptors, Adrenergic
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Receptors, Dopamine D2
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Serotonin 5-HT1 Receptor Agonists
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Levodopa
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Thioctic Acid
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Oxidopamine