1-(2'-Bromobenzyl)-6,7-dihydroxy-N-methyl-tetrahydroisoquinoline and 1,2-Demethyl-nuciferine as Agonists in Human D2 Dopamine Receptors.,Journal of Natural Products

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1-(2'-Bromobenzyl)-6,7-dihydroxy-N-methyl-tetrahydroisoquinoline and 1,2-Demethyl-nuciferine as Agonists in Human D2 Dopamine Receptors.
Journal of Natural Products ( IF 3.3 ) Pub Date : 2020-01-14 , DOI: 10.1021/acs.jnatprod.9b00921
Andrea G Silva ₁ , Laura Vila ₂ , Patrice Marques _{2,

3,

4} , Laura Moreno _{3,

4} , Mabel Loza ₁ , María-Jesús Sanz _{2,

3,

4} , Diego Cortes _{3,

4} , Marián Castro ₁ , Nuria Cabedo _{2,

3,

4}

Affiliation

Certain D2-like dopamine receptor (DR) agonists are useful therapeutically as antiparkinsonian drugs, whereas D2-like DR antagonists or partial agonists are proven effective as antipsychotics. Two isoquinoline derivatives, 1-(2'-bromobenzyl)-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 (Ki) for hD2, hD3, and hD4 DR within the nanomolar range. The trends in affinity were hD4R ≫ hD3R > hD2R for Br-BTHIQ (1) and hD2R > hD4R > hD3R 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 μM, 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.

中文翻译：

1-（2'-溴苄基）-6,7-二羟基-N-甲基-四氢异喹啉和1,2-脱甲基-核苷在人类D2多巴胺受体中的激动剂。

某些D2类多巴胺受体（DR）激动剂可作为抗帕金森病药物在治疗上使用，而D2类DR拮抗剂或部分激动剂被证明可有效用作抗精神病药。本文合成了两种异喹啉衍生物，即1-（2'-溴苄基）-6,7-二羟基-N-甲基-四氢异喹啉（Br-BTHIQ，1）和1,2-脱甲基-Nuciferine（aporphine，2），并且评估了它们在克隆的人D2R，D3R和D4R亚型中的多巴胺能亲和力以及它们作为激动剂/拮抗剂的行为。他们显示了在纳摩尔范围内对hD2，hD3和hD4 DR的亲和力值（Ki）。对Br-BTHIQ（1）的亲和力趋势为：hD4R≫ hD3R> hD2R（1），而对于1,2-脱甲基-核酸（2），hD2R> hD4R> hD3R。在人D2R上进行的环磷酸腺苷信号转导的功能分析表明，Br-BTHIQ（1）具有部分激动剂作用，而Aph（2）具有完全激动剂作用，最大有效浓度分别为2.95和10.2μM。因此，异喹啉1和2均已作为合成新治疗药物的先导分子出现，这些药物最终可能分别可用于预防精神分裂症和帕金森氏病。

更新日期：2020-01-14

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