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: 11.54). 09/2007; 28(8):390-6. DOI: 10.1016/
Source: PubMed


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
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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 requirement for blood flow. The heart is able to respond to these changing needs by adjusting cardiac output based on cues emitted by circulating catecholamine levels. Cardiac β-adrenoceptors transduce the signal produced by catecholamine stimulation via Gs proteins to their downstream effectors to increase heart contractility. During heart failure, cardiac output is insufficient to meet the needs of the body; catecholamine levels are high and β-adrenoceptors become hyperstimulated. The hyperstimulated β1-adrenoceptors induce a cardiotoxic effect, which could be counteracted by the cardioprotective effect of β2-adrenoceptor-mediated Gi signalling. However, β2-adrenoceptor-Gi signalling negates the stimulatory effect of the Gs signalling on cardiomyocyte contraction and further exacerbates cardiodepression. Here, further to the localization of β1- and β2-adrenoceptors and β2-adrenoceptor-mediated β-arrestin signalling in cardiomyocytes, we discuss features of the dysregulation of β-adrenoceptor subtype signalling in the failing heart, and conclude that Gi-biased β2-adrenoceptor signalling is a pathogenic pathway in heart failure that plays a crucial role in cardiac remodelling. In contrast, β2-adrenoceptor-Gs signalling increases cardiomyocyte contractility 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 increase our understanding of the pathophysiology of diseases and in the development of novel therapies.
    Full-text · Article · Oct 2014 · British Journal of Pharmacology
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    • "DHX exhibits more than ten-fold higher affinity and potency at the D 1 receptor than dopamine; and, exhibits full intrinsic activity in every system in which it has been tested to date (Brewster et al. 1990; Mottola et al. 1992; Salmi et al. 2004; Watts et al. 1995). DHX has about ten-fold selectivity for the D 1 versus the D 2 receptor (Mottola et al. 1992), and, at the D 2 receptor it is functionally selective with high bias for regulation of adenylate cyclase versus potassium channels (Gay et al. 2004; Kilts et al. 2002; Mailman 2007; Mottola et al. 2002). When DHX entered development in 2002, it was assigned the label DAR-0100, and the active (both at D 1 and D 2 ) diastereomer (Knoerzer et al. 1994; Mottola et al. 1996) assigned the label, DAR-0100A. "
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    ABSTRACT: Pharmacological enhancement of prefrontal D1 dopamine receptor function remains a promising therapeutic approach to ameliorate schizophrenia-spectrum working memory deficits, but has yet to be rigorously evaluated clinically. This proof-of-principle study sought to determine whether the active enantiomer of the selective and full D1 receptor agonist dihydrexidine (DAR-0100A) could attenuate working memory impairments in unmedicated patients with schizotypal personality disorder (SPD). We performed a randomized, double-blind, placebo-controlled trial of DAR-0100A (15 mg/150 ml of normal saline administered intravenously over 30 min) in medication-free patients with SPD (n=16) who met criteria for cognitive impairment (i.e., scoring below the 25(th) percentile on tests of working memory). We employed two measures of verbal working memory that are salient to schizophrenia-spectrum cognitive deficits, and clinical data implicate as being associated with prefrontal D1 availability: 1) the Paced Auditory Serial Addition Test (PASAT); and 2) the N-back test (ratio of 2-back:0-back scores). Study procedures occurred over four consecutive days with working memory testing on Days 1 and 4, and DAR-0100A/placebo administration on Days 2-4. Treatment with DAR-0100A was associated with significantly improved PASAT performance relative to placebo, with a very large effect size (Cohen's d=1.14 for both tests). Performance on the N-back ratio was also significantly improved, however, this effect rested on both a non-significant enhancement and diminution of 2-back and 0-back performance, respectively; therefore interpretation of this finding is more complicated. DAR-0100A was generally well tolerated, with no serious medical or psychiatric adverse events; common side-effects were mild-to-moderate and transient, consisting mainly of sedation, lightheadedness, tachycardia, and hypotension; however, we were able to minimize these effects, without altering the dose, with supportive measures, e.g., co-administered normal saline. Although preliminary, these findings lend further clinical support to the potential of D1 receptor agonists to treat schizophrenia-spectrum working memory impairments. These data suggest a need for further studies with larger group sizes, serum DAR-0100A levels, and a more comprehensive neuropsychological battery.Neuropsychopharmacology accepted article preview online, 30 July 2014; doi:10.1038/npp.2014.192.
    Full-text · Article · Jul 2014 · Neuropsychopharmacology: official publication of the American College of Neuropsychopharmacology
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    • "Dopamine receptors were originally classified on the basis of their coupling to adenylate cyclase (Kebabian et al., 1972; Garau et al., 1978; Kebabian and Calne, 1979), and this canonical signaling of the D 1 -like receptors (D 1 , D 5 ) is thought to involve coupling to the G proteins Ga OLF or Ga S (Neve et al., 2004; Mailman and Huang, 2007). Thus, the cAMP resulting from D 1 receptor activation could initiate a host of downstream cascades, such as those engaged by the activation of cAMP/protein kinase A signaling. "
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    ABSTRACT: Despite numerous studies showing therapeutic potential, no central dopamine D1 receptor ligand has ever been approved because of potential limitations such as hypotension, seizures, and tolerance. Functional selectivity has been widely recognized as providing a potential mechanism to develop novel therapeutics from existing targets, and a highly-biased functionally selective D1 ligand might overcome some of the past limitations. SKF-83959 is reported to be a highly biased D1 ligand, having full agonism at D1-mediated activation of phospholipase C (PLC) signaling (via GαQ) and antagonism at D1-mediated adenylate cyclase signaling (via GαOLF/S). For this reason, numerous studies have used this compound to elucidate the physiological role of D1-PLC signaling, including a novel molecular mechanism (GαQ-PLC activation via D1:D2 heterodimers). There is, however, contradictory literature that suggests that SKF-83959 is actually a partial agonist at both D1-mediated adenylate cyclase and β-arrestin recruitment. Moreover, the D1-mediated of PLC stimulation has also been questioned. This perspective reviews 30 years of relevant literature, and proposes that the data strongly favor alternate hypotheses, first that SKF-83959 is a typical D1 partial agonist, and second, that the reported activation of PLC by SKF-83959 and related benzazepines likely is due to off-target effects, not actions at D1 receptors. If these hypotheses are supported by future studies, it would suggest that caution should be used regarding the role of PLC and downstream pathways in D1 signaling.
    Preview · Article · Jul 2014 · Journal of Pharmacology and Experimental Therapeutics
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