1-(2 '-Bromobenzyl)-6,7-dihydroxy-N-methyl-tetrahydroisoquinoline and 1,2-Demethyl-nuciferine as Agonists in Human D-2 Dopamine Receptors

Autores de INCLIVA

• 

  Laura Vila Dasí

  Autor

• Patrice Gomes Marques

  Autor

• 

  Maria Jesus Sanz Ferrando

  Autor

• 

  Nuria Cabedo Escrig

  Autor

Participantes ajenos a INCLIVA

• Silva, AG
• Moreno, L
• Loza, M
• Cortes, D
• Castro, M

Grupos y Plataformas de I+D+i

• Grupo de Investigación en Inflamación

  

  Leading Researcher

  Maria Jesus Sanz Ferrando

Abstract

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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