GPCR functional selectivity has therapeutic impact

Neurosciences Hospital, University of North Carolina School of Medicine, Chapel Hill, NC 27599-7160, USA.
Trends in Pharmacological Sciences (Impact Factor: 9.99). 09/2007; 28(8):390-6. DOI: 10.1016/
Source: PubMed

ABSTRACT Many in vitro data show that some ligands can cause the differential activation of signaling pathways mediated by a single receptor (termed 'functional selectivity'). It remains unclear, however, whether functionally selective properties are meaningful in vivo. Data obtained with experimental compounds that are functionally selective at the dopamine D2L receptor in vitro suggest that these properties might predict atypical behavioral actions. Moreover, the antipsychotic drug aripiprazole is commonly thought to be a D2 partial agonist, but data clearly show that aripiprazole is functionally selective in vitro. It is proposed that the effects of aripiprazole in animal models and humans can be reconciled only with its functionally selective D2 properties, not its partial D2 agonism. Together, these data provide support for the hypothesis that compounds with functionally selective properties in vitro are likely to have novel actions in vivo, opening doors to new avenues of drug discovery.

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Available from: Richard B Mailman, Aug 16, 2015
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    • "Understanding the signalling mechanisms of these receptor systems is the key to the development of medications beyond β-blockers, angiotensin receptor blockers and ACEI. In particular, a recently described phenomenon named 'functional selectivity' has been highly regarded as a new avenue for drug discovery based on GPCR signal transduction (Kenakin, 2007; Mailman, 2007; Urban et al., 2007; Violin and Lefkowitz, 2007; Woo and Xiao, 2012). However, GPCR signal transduction is dauntingly complex with multiple intracellular signalling cascades operating integrally to produce an orchestrated biological response. "
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    ABSTRACT: The body is constantly faced with a dynamic demand of blood flow. The heart is able to respond to these changing needs by adjusting cardiac output based on the cues of the circulating catechnolamine levels. Cardiac β-adrenoceptors transduce the signal of catecholamine stimulation via Gs proteins to their downstream effectors to increase heart contractility. During heart failure, cardiac output is insufficient to meet the need of the body. Catecholamine levels are high and β-adrenoceptors become hyperstimulated. The hyperstimulated β1 -adrenoceptors induce a cardiotoxic effect which could be countered by the cardioprotective effect mediated by the β2 -adrenoceptor-mediated Gi signalling. However, the β2 -adrenoceptor-Gi signalling negates the stimulatory effect of the Gs signalling on cardiomyocyte contraction and further deepens cardiodepression. Here, beyond the localization of β1 -AR and β2 -AR and β2 -AR-mediated β-arrsetin signaling in cardiomyocytes, we discuss the features of the dysregulation of the β-adrenoceptor subtype signalling in the failing heart, leading to the conclusion that Gi -biased β2 -adrenoceptor signalling is a pathogenic pathway in heart failure and that it plays a crucial role in cardiac remodelling. In contrast, the β2 -adrenoceptor-Gs signalling mediates cardiomyocyte contractility increase without causing cardiotoxicity. Finally, we discuss a novel therapeutic approach for heart failure using a Gs -biased β2 -adrenoceptor agonist and a β1 -adrenoceptor antagonist in combination. This combination treatment normalizes the β-adrenoceptor subtype signalling in the failing heart and produces therapeutic effects that outperform traditional heart failure therapies in animal models. The present review illustrates how the concept of biased signalling can be applied to better our understanding of the pathophysiology of diseases and in the development of novel therapies.
    British Journal of Pharmacology 10/2014; DOI:10.1111/bph.12965 · 4.99 Impact Factor
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    • "D2Rs couple to numerous signaling pathways, mediated by G βγ , βarrestins , and scaffolding proteins (Bonci and Hopf, 2005). D2R ligands possess functional selectivity for these pathways (Mailman, 2007), and the dose-dependence of quinpirole likely varies across these pathways (Urban et al., 2007). Notably, effects mediated by βarrestin have a timecourse ~10 min (Ahn et al., 2004), similar to what we observed. "
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    ABSTRACT: Dopamine D2 receptors (D2Rs) play a major role in the function of the prefrontal cortex (PFC), and may contribute to prefrontal dysfunction in conditions such as schizophrenia. Here we report that in mouse PFC, D2Rs are selectively expressed by a subtype of layer V pyramidal neurons that have thick apical tufts, prominent h-current, and subcortical projections. Within this subpopulation, the D2R agonist quinpirole elicits a novel afterdepolarization that generates voltage fluctuations and spiking for hundreds of milliseconds. Surprisingly, this afterdepolarization is masked in quiescent brain slices, but is readily unmasked by physiologic levels of synaptic input which activate NMDA receptors, possibly explaining why this phenomenon has not been reported previously. Notably, we could still elicit this afterdepolarization for some time after the cessation of synaptic stimulation. In addition to NMDA receptors, the quinpirole-induced afterdepolarization also depended on L-type Ca(2+) channels and was blocked by the selective L-type antagonist nimodipine. To confirm that D2Rs can elicit this afterdepolarization by enhancing Ca(2+) (and Ca(2+)-dependent) currents, we measured whole-cell Ca(2+) potentials that occur after blocking Na(+) and K(+) channels, and found quinpirole enhanced these potentials, while the selective D2R antagonist sulpiride had the opposite effect. Thus, D2Rs can elicit a Ca(2+)-channel-dependent afterdepolarization that powerfully modulates activity in specific prefrontal neurons. Through this mechanism, D2Rs might enhance outputs to subcortical structures, contribute to reward-related persistent firing, or increase the level of noise in prefrontal circuits.
    The Journal of Neuroscience : The Official Journal of the Society for Neuroscience 04/2012; 32(14):4959-71. DOI:10.1523/JNEUROSCI.5835-11.2012 · 6.75 Impact Factor
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    • "Although this signaling bias runs counter to classic concepts of drugreceptor mechanisms, it has become firmly established and has been demonstrated for dozens of receptors (Urban et al., 2007; Neve, 2009). As well as being heuristically interesting, it is also generally appreciated that functionally selective ligands with the " correct " bias may yield improved therapeutic indices versus drugs that are " typical " agonists or antagonists (Mailman, 2007). It is generally believed that the functionally selected properties of a ligand are a result of the differential stabilization and/or induction of active states of the target receptor that are associated with specific signaling pathways (Kenakin, 1995, 2007; Urban et al., 2007). "
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    ABSTRACT: 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.
    Molecular pharmacology 03/2012; 81(6):820-31. DOI:10.1124/mol.111.075457 · 4.12 Impact Factor
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