Functional Selectivity and Classical Concepts of Quantitative Pharmacology

Urban, Jonathan D.; Clarke, William P.; Zastrow, Mark von; Nichols, David E.; Kobilka, Brian K.; Weinstein, Harel; Javitch, Jonathan A.; Roth, Bryan L.; Christopoulos, Arthur; Sexton, Patrick M.; Miller, Keith J.; Spedding, Michael; Mailman, Richard B.

doi:10.1124/jpet.106.104463

Cited by 992 publications

(950 citation statements)

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“…The reasons why tolerance develops to the effects of some 5-HT 2C receptor agonists but not others are not known. It may be that any variations in tolerance profiles between these 5-HT 2C receptor agonists relate to how these compounds differentially activate distinct intracellular signalling pathways coupled to 5-HT 2C receptors (eg Berg et al, 2001;Stout et al, 2002), a phenomenon termed functional selectivity (Urban et al, 2007).…”

Section: Discussionmentioning

confidence: 99%

The 5-HT2C Receptor Agonist Ro60-0175 Reduces Cocaine Self-Administration and Reinstatement Induced by the Stressor Yohimbine, and Contextual Cues

Fletcher

Rizos

Sinyard

et al. 2007

Neuropsychopharmacol

112

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Previously, we showed that the 5-HT 2C receptor agonist Ro60-0175 reduces cocaine self-administration, and the ability of cocaine to reinstate responding after extinction of drug-seeking behavior. The present experiments extended these findings further by determining whether the effects of Ro60-0175 on self-administration were sustained with repeated treatment, and whether Ro60-0175 altered reinstatement induced by the pharmacological stressor yohimbine, or by the context in which self-administration occurred. In Experiment 1, Ro60-0175 (1 mg/kg, s.c.) reduced cocaine (0.25 mg/infusion) self-administration maintained by a progressive ratio schedule. This reduction was sustained over eight daily injections. In Experiment 2, rats self-administered cocaine in daily 2 h sessions for 15 days on a FR1 schedule. Following extinction, yohimbine (1 mg/kg, i.p.) reinstated responding, and this effect was reduced dose dependently by Ro60-0175 (0.3-3 mg/kg, s.c.). In Experiment 3, rats were trained to respond for cocaine on a FR1 schedule in a distinct environmental context (A); responding was then extinguished in a different context (B). Reinstatement tests occurred in either context A or B.Responding was reinstated only when rats were tested in the original self-administration context (A). This reinstatement was reduced dose dependently by Ro60-0175. All effects of Ro60-0175 were blocked by the 5-HT 2C receptor antagonist SB242084. Thus, Ro60-0175, acting via 5-HT 2C receptors, reduces cocaine self-administration and cocaine-seeking triggered by a stressor and by drug-associated cues. The effects of Ro60-0175 do not exhibit tolerance within the 8-day test period. These results indicate that selective 5-HT 2C receptor agonists may be a useful pharmacological strategy for treatment of drug abuse.

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Section: Discussionmentioning

confidence: 99%

The 5-HT2C Receptor Agonist Ro60-0175 Reduces Cocaine Self-Administration and Reinstatement Induced by the Stressor Yohimbine, and Contextual Cues

Fletcher

Rizos

Sinyard

et al. 2007

Neuropsychopharmacol

112

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“…The concept of selective receptor modulators is probably most widely recognized in the nuclear receptor field where it has had an enormous impact on steroid receptor targeted therapeutics (Jordan, 2007). However, recent studies have demonstrated that the general concept of selective receptor modulators also applies to GPCRs (for recent reviews see (Galandrin et al, 2007;Kenakin, 2004;Neubig, 2007;Perez and Karnik, 2005;Urban et al, 2007;Violin and Lefkowitz, 2007)) and this evolution in our understanding again promises to have important consequences for drug development (Mailman, 2007). New terms have been coined to describe the idea that agonists can selectively activate different signaling pathways and responses via a single GPCR.…”

Section: Ligand Binding and Functional Selectivity In G Protein Couplmentioning

confidence: 99%

Selective agonism in somatostatin receptor signaling and regulation

Schönbrunn¹

2008

Molecular and Cellular Endocrinology

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SummaryThe five somatostatin receptor subtypes, named sst1 to sst5, activate both distinct and common signaling pathways and exhibit different patterns of receptor regulation. Until recently it was believed that once a particular somatostatin receptor was activated by an agonist, all the downstream signaling and regulatory effects characteristic of that receptor subtype in that cellular environment would be triggered. Thus, differences in the actions of somatostatin analogs between tissues were attributed to variability in the nature and concentration of the sst receptor subtypes and effectors expressed in different targets. However, agonists have recently been shown to exhibit functional selectivity at individual sst receptors such that they can elicit a subset of that receptor's potential effects, a property known as biased agonism. This review will summarize the evidence for functionally selective somatostatin receptor agonists and discuss the implications and promise of these new findings.

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“…For many members of this receptor family it is now well established that they oscillate among multiple conformations which can be differentially stabilized by ligands thus permitting access to only a subset of the complete repertoire of receptor behaviors [2][3][4][5][6][7][8] . This phenomenon, also referred to as biased agonism, functional selectivity or signal trafficking, has an important impact on GPCR drug discovery because it raises the possibility to design signaling pathway-specific therapeutics.…”

Section: Introductionmentioning

confidence: 99%