Although functional selectivity is now widely accepted, the molecular basis is poorly understood. We have studied how aspects of transmembrane region 5 (TM5) of the dopamine D(2L) receptor interacts with three rationally selected rigid ligands (dihydrexidine, dinapsoline, and dinoxyline) and the reference compounds dopamine and quinpirole. As was expected from homology modeling, mutation of three TM5 serine residues to alanine (S5.42A, S5.43A, S5.46A) had little effect on antagonist affinity. All three mutations decreased the affinity of the agonist ligands to different degrees, S5.46A being somewhat less affected. Four functions [adenylate cyclase (AC), extracellular signal-regulated kinase 1/2 phosphorylation (MAPK), arachidonic acid release (AA), and guanosine 5'-O-(3-thio)triphosphate binding (GTPγS)] were assessed. The intrinsic activity (IA) of quinpirole was unaffected by any of the mutations, whereas S5.42A and S5.46A mutations abolished the activity of dopamine and the three rigid ligands, although dihydrexidine retained IA at MAPK function only with S5.42A. Remarkably, S5.43A did not markedly affect IA for AC and MAPK for any of the ligands and eliminated AA activity for dinapsoline and dihydrexidine but not dinoxyline. These data suggest that this mutation did not disrupt the overall conformation or signaling ability of the mutant receptors but differentially affected ligand activation. Computational studies indicate that these D(2) agonists stabilize multiple receptor conformations. This has led to models showing the stabilized conformations and interhelical and receptor-ligand contacts corresponding to the different activation pathways stabilized by various agonists. These data provide a basis for understanding D(2L) functional selectivity and rationally discovering functionally selective D(2) drugs.

2009-03-01·Medicinal Research Reviews1区 · 医学

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

1区 · 医学

Review

作者: Zhang, Ao ; Zhang, Jing ; Xiong, Bing ; Zhen, Xuechu

AbstractThe dopamine (DA) D1 receptor is the most highly expressed DA receptor subtype among the DA receptor family. Although the first DA D1 receptor selective ligand SCH‐23390 (1) was introduced more than two decades ago, clinically useful D1 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 D1 receptor. Since then, a number of D1 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 D1 receptor agonists. © 2008 Wiley Periodicals, Inc. Med Res Rev, 29, No. 2, 272–294, 2009

2007-02-01·Neuropharmacology2区 · 医学

Functional selectivity of dopamine D1 receptor agonists in regulating the fate of internalized receptors

2区 · 医学

Article

作者: Brown, Justin T. ; Mailman, Richard B. ; Goddard, William A. ; Ryman-Rasmussen, Jessica P. ; Oloff, Scott ; Griffith, Adam ; Vaidehi, Nagarajan

Recently, we demonstrated that D(1) agonists can cause functionally selective effects when the endpoints of receptor internalization and adenylate cyclase activation are compared. The present study was designed to probe the phenomenon of functional selectivity at the D(1) receptor further by testing the hypothesis that structurally dissimilar agonists with efficacies at these endpoints that equal or exceed those of dopamine would differ in ability to influence receptor fate after internalization, a functional endpoint largely unexplored for the D(1) receptor. We selected two novel agonists of therapeutic interest that meet these criteria (the isochroman A-77636, and the isoquinoline dinapsoline), and compared the fates of the D(1) receptor after internalization in response to these two compounds with that of dopamine. We found that dopamine caused the receptor to be rapidly recycled to the cell surface within 1h of removal. Conversely, A-77636 caused the receptor to be retained intracellularly up to 48 h after agonist removal. Most surprisingly, the D(1) receptor recovered to the cell surface 48 h after removal of dinapsoline. Taken together, these data indicate that these agonists target the D(1) receptor to different intracellular trafficking pathways, demonstrating that the phenomenon of functional selectivity at the D(1) receptor is operative for cellular events that are temporally downstream of immediate receptor activation. We hypothesize that these differential effects result from interactions of the synthetic ligands with aspects of the D(1) receptor that are distal from the ligand binding domain.

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适应症	最高研发状态	国家/地区	公司	日期
注意缺陷障碍伴多动	药物发现	美国	DarPharma, Inc.	-
帕金森病	药物发现	美国	DarPharma, Inc.	-
精神分裂症	药物发现	美国	DarPharma, Inc.	-