Novel Strategies To Activate the Dopamine D1 Receptor: Recent Advances in Orthosteric Agonism and Positive Allosteric Modulation.

Abstract:

:The five dopamine receptor subtypes (D1-5) are activated by the endogenous catecholamine dopamine. Sustained research has sought to identify selective ligands for receptor subtypes. In particular, activation of the D1 receptor has attracted attention due to its promising role in neurological diseases. Initial attempts to identify agonists yielded catechol derivatives, mimicking dopamine, with suboptimal DMPK parameters and low selectivity over the D5 subtype. However, more recent efforts to identify ligands capable of activating the D1 receptor have made substantial progress with the identification of non-catechol agonists with suitable properties to progress to clinical studies. In addition, several research groups have identified positive allosteric modulators that offer new potential. Furthermore, structural studies have surprisingly uncovered two potential allosteric binding sites, the most characterized of which appears to be on intracellular loop 2 (ICL2). This review highlights the recent progress in the field, covering both orthosteric and allosteric modes of activation, discusses the elucidation of the allosteric binding sites, and summarizes the clinical development status of various compounds.

journal_name

J Med Chem

authors

Hall A,Provins L,Valade A

doi

10.1021/acs.jmedchem.8b01767

subject

Has Abstract

pub_date

2019-01-10 00:00:00

pages

128-140

issue

1

eissn

0022-2623

issn

1520-4804

journal_volume

62

pub_type

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