(5aR,11bS)-4,5,5a,6,7,11b-Hexahydro-2-propyl-3-thia-5-azacyclopent-1-ena[c]phenanthrene-9,10-diol (A-86929): a potent and selective dopamine D1 agonist that maintain behavioral efficacy following repeated administration and characterization of its diacetyl prodrug (ABT-431)

Michaelides, Michel; Hong, Yufeng; DiDomenico, Stanley; Asin, Karen E.; Britton, Donald R.; Lin, Chun Wel; Williams, Michael; Shiosaki, Kazumi

doi:10.1021/jm00018a002

Cited by 59 publications

(40 citation statements)

References 3 publications

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“…64 The NH compound 31a (A-86929) possess high affinity for the cloned human D 1 receptor with a K i of 49 nM. Similar to 27a, this compound also has full intrinsic activity relative to DA in stimulating adenylate cyclase (EC 50 , 9 nM).…”

Section: B Dihydrexidine and Its Polycyclic Analoguesmentioning

confidence: 99%

Dopamine D₁ receptor ligands: Where are we now and where are we going

Zhang¹,

Xiong²,

Zhen³

et al. 2008

Medicinal Research Reviews

132

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The dopamine (DA) D(1) receptor is the most highly expressed DA receptor subtype among the DA receptor family. Although the first DA D(1) receptor selective ligand SCH-23390 (1) was introduced more than two decades ago, clinically useful D(1) receptor selective ligands are rare. A renewed interest was ignited in the early 1990s by Nichols and Mailman who developed dihydrexidine (27a), the first high affinity full efficacy agonist for the D(1) receptor. Since then, a number of D(1) receptor agonists with full intrinsic activity, including A-86929 (31a), dinapsoline (32a), dinoxyline (34a), and doxanthrine (35a) were identified. These compounds all contain a conformationally rigid structure. However, the fate of such ligands for clinical use as treatments of Parkinson's disease and other related CNS disorders is not optimistic since the clinical trial with dihydrexidine (27a) was not successful. Further investigations on other compounds which are currently in the discovery stage will be crucial for determining the future of the D(1) receptor agonists.

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Section: B Dihydrexidine and Its Polycyclic Analoguesmentioning

confidence: 99%

Dopamine D₁ receptor ligands: Where are we now and where are we going

Zhang¹,

Xiong²,

Zhen³

et al. 2008

Medicinal Research Reviews

132

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“…A86929 is similar in structure and pharmacological properties to dihydrexidine (85, 86). Like dihydrexidine, ABT-431 caused dramatic antiparkinsonian effects (74, 86, 87), but like dihydrexidine, even the prodrug ABT-431 had poor oral bioavailability.…”

Section: Approaches To Modulating Dopamine Functionmentioning

confidence: 99%

Novel Dopamine Therapeutics for Cognitive Deficits in Schizophrenia

Arnsten

Girgis

Gray

et al. 2017

Biological Psychiatry

141

110

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Schizophrenia is characterized by profound cognitive deficits that are not alleviated by currently available medications. Many of these cognitive deficits involve dysfunction of the newly evolved, dorsolateral prefrontal cortex (dlPFC). The brains of patients with schizophrenia show evidence of dlPFC pyramidal cell dendritic atrophy, likely reductions in cortical dopamine (DA), and possible changes in DA D1 receptors (D1R). It has been appreciated for decades that optimal levels of DA are essential for dlPFC working memory function, with many beneficial actions arising from D1R stimulation. D1R are concentrated on dendritic spines in the primate dlPFC, where their stimulation produces an inverted U dose-response on dlPFC neuronal firing and cognitive performance during working memory tasks. Research in both academia and the pharmaceutical industry has led to the development of selective D1 agonists, e.g., the first full D1 agonist, dihydrexidine, which at low doses improved working memory in monkeys. Dihydrexidine has begun to be tested in patients with schizophrenia or schizotypal disorder. Initial results are encouraging, but studies are limited by the pharmacokinetics of the drug. These data have, however, spurred efforts towards the discovery and development of improved or novel new compounds, including D1 agonists with better pharmacokinetics, functionally selective D1 ligands, and D1R positive allosteric modulators. One or several of these approaches should allow optimization of the beneficial effects of D1R stimulation in the dlPFC that can be translated into clinical practice.

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“…Although numerous D 2 -like ligands have been the subject of clinical studies, the only reports of studies in humans for selective D 1 agonists are for DHX (Brewster et al, 1990; Lovenberg et al, 1989; Mottola et al, 1992) and ABT-431 (nee A83959) (Michaelides et al, 1995; Shiosaki et al, 1996). Both compounds have similar pharmacology and have been shown to have profound antiparkinson activity (Giardina and Williams, 2001; Haney et al, 1999; Okumu et al, 2002; Rascol et al, 1999; Rascol et al, 2001; Self et al, 2000).…”

Section: D1-like Signalingmentioning

confidence: 99%

Dopamine Receptor Signaling and Current and Future Antipsychotic Drugs

Boyd

Mailman

2012

Handbook of Experimental Pharmacology

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All currently efficacious antipsychotic drugs have as part of their mechanism the ability to attenuate some or all of their signaling through the dopamine D2 receptor. More recently, the dopamine D1 receptor has been hypothesized to be a promising target for the treatment of negative and/or cognitive aspects of schizophrenia that are not improved by current antipsychotics. Although cAMP has been presumed to be the primary messenger for signaling through the dopamine receptors, the last decade has unveiled a complexity that has provided exciting avenues for the future discovery of antipsychotic drugs (APDs). We review the signaling mechanisms of currently approved APDs at dopamine D2 receptors, and note that aripiprazole is a compound that is clearly differentiated from other approved drugs. Although aripiprazole has been postulated to cause dopamine stabilization due to its partial D2 agonist properties, a body of literature suggests that an alternate mechanism, functional selectivity, is of primary importance. Finally, we review the signaling at dopamine D1 receptors, and the idea that drugs that activate D1 receptors may have use as APDs for improving negative and cognitive symptoms. We address the current state of drug discovery in the D1 area, and its relationship to novel signaling mechanisms. Our conclusion is that although the first APD targeting dopamine receptors was discovered more than a half-century ago, recent research advances offer the possibility that novel and/or improved drugs will emerge in the next decade.

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(5aR,11bS)-4,5,5a,6,7,11b-Hexahydro-2-propyl-3-thia-5-azacyclopent-1-ena[c]phenanthrene-9,10-diol (A-86929): a potent and selective dopamine D1 agonist that maintain behavioral efficacy following repeated administration and characterization of its diacetyl prodrug (ABT-431)

Cited by 59 publications

References 3 publications

Dopamine D₁ receptor ligands: Where are we now and where are we going

Dopamine D₁ receptor ligands: Where are we now and where are we going

Novel Dopamine Therapeutics for Cognitive Deficits in Schizophrenia

Dopamine Receptor Signaling and Current and Future Antipsychotic Drugs

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(5aR,11bS)-4,5,5a,6,7,11b-Hexahydro-2-propyl-3-thia-5-azacyclopent-1-ena[c]phenanthrene-9,10-diol (A-86929): a potent and selective dopamine D1 agonist that maintain behavioral efficacy following repeated administration and characterization of its diacetyl prodrug (ABT-431)

Cited by 59 publications

References 3 publications

Dopamine D1 receptor ligands: Where are we now and where are we going

Dopamine D1 receptor ligands: Where are we now and where are we going

Novel Dopamine Therapeutics for Cognitive Deficits in Schizophrenia

Dopamine Receptor Signaling and Current and Future Antipsychotic Drugs

Contact Info

Product

Resources

About

Dopamine D₁ receptor ligands: Where are we now and where are we going

Dopamine D₁ receptor ligands: Where are we now and where are we going