Return of D4 Dopamine Receptor Antagonists in Drug Discovery,Journal of Medicinal Chemistry

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Return of D4 Dopamine Receptor Antagonists in Drug Discovery
Journal of Medicinal Chemistry ( IF 6.8 ) Pub Date : 2017-05-10 00:00:00 , DOI: 10.1021/acs.jmedchem.7b00151
Craig W. Lindsley , Corey R. Hopkins ₁

Affiliation

The dopamine D₄ receptor garnered a great deal of interest in the early 1990s when studies showed the atypical antipsychotic clozapine possessed higher affinity for D₄, relative to other dopamine receptor subtypes, and that this activity might underlie the unique clinical efficacy of clozapine. Unfortunately, D₄ antagonists that were developed for schizophrenia failed in the clinic. Thus, D₄ fell out of favor as a therapeutic target, and work in this area was silent for decades. Recently, D₄ ligands with improved selectivity for D₄ against not only D_1–3,5 but also other biogenic amine targets have emerged, and D₄ is once again in the spotlight as a novel target for both addiction and Parkinson’s disease (PD), as well as other emerging diseases. This report will review the historical data for D₄, review the known D₄ ligands, and then highlight new data supporting a role for D₄ inhibition in addiction, PD, and cancer.

中文翻译：

D ₄多巴胺受体拮抗剂在药物发现中的回归

多巴胺D ₄受体在1990年代初引起了极大的兴趣，当时研究表明非典型抗精神病药氯氮平相对于其他多巴胺受体亚型对D ₄具有更高的亲和力，并且这种活性可能是氯氮平独特的临床疗效的基础。不幸的是，为精神分裂症开发的D ₄拮抗剂在临床上失败了。因此，D ₄失去了作为治疗靶标的支持，几十年来，该领域的研究一直保持沉默。最近，出现了对D ₄选择性提高的D ₄配体，不仅针对D _1–3,5，而且还针对其他生物胺靶标，并且D ₄作为成瘾和帕金森氏病（PD）以及其他新兴疾病的新型靶标，它再次受到关注。该报告将回顾D ₄的历史数据，回顾已知的D ₄配体，然后重点介绍支持D ₄抑制在成瘾，PD和癌症中起作用的新数据。

更新日期：2017-06-28

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