Journal
JOURNAL OF NATURAL PRODUCTS
Volume 83, Issue 1, Pages 127-133Publisher
AMER CHEMICAL SOC
DOI: 10.1021/acs.jnatprod.9b00921
Keywords
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Funding
- Spanish Ministry of Economy and Competiveness [SAF2014-57138-C2-1-R, SAF2014-57845-R, SAF2017-89714-R, CP15/00150, PI18/01450]
- Carlos III Health Institute
- European Regional Development Fund
- Miguel Servet Program, Carlos III Institute of Health
- European Fund for Regional Development Fund
- European Social Fund
- Spanish Ministry of Economy and Competitiveness (FPI)
- Xunta de Galicia (Spain)
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Certain D-2-like dopamine receptor (DR) agonists are useful therapeutically as antiparkinsonian drugs, whereas D-2-like DR antagonists or partial agonists are proven effective as antipsychotics. Two isoquinoline derivatives, 1-(2'-bromobenzy1)-6,7-dihydroxy-N-methyl-tetrahydroisoquinoline (Br-BTHIQ, 1) and 1,2-demethyl-nuciferine (aporphine, 2), were herein synthesized, and their dopaminergic affinity in cloned human D2R, D3R, and D4R subtypes and their behavior as agonists/antagonists were evaluated. They showed affinity values (K-i) for hD(2), hD(3), and hD(4) DR within the nanomolar range. The trends in affinity were hD(4)R >> hD(3)R > hD(2)R for Br-BTHIQ (1) and hD(2)R > hD(4)R > hD(3)R for 1,2-demethyl-nuciferine (2). The functional assays of cyclic adenosine monophosphate signaling at human D2R showed a partial agonist effect for Br-BTHIQ (1) and full agonist behavior for aporphine (2), with half maximal effective concentration values of 2.95 and 10.2 mu M, respectively. Therefore, both isoquinolines 1 and 2 have emerged as lead molecules for the synthesis of new therapeutic drugs that ultimately may be useful to prevent schizophrenia and Parkinson's disease, respectively.
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