Atypical antipsychotics and inverse agonism at 5-HT&lt;sub&gt;2&lt;/sub&gt; receptors

Sullivan, Laura C.; Clarke, William P.; Berg, Kelly A.

doi:10.2174/1381612821666150605111236

Cited by 54 publications

(31 citation statements)

References 80 publications

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“…Constitutive receptor activity, like agonist-stimulated activity, can differentially activate multiple cellular signaling mechanisms, including those that lead to desensitization (loss of responsiveness). As a result, receptor systems can exist in a state of constitutive desensitization (Pei et al, 1994;Berg et al, 1999;Barak et al, 2001Barak et al, , 2003Sullivan et al, 2015b) where responsiveness to agonist stimulation is reduced. Prolonged reduction in constitutive receptor activity produced by treatment with an inverse agonist allows constitutively desensitized receptor systems to resensitize, thereby increasing responsiveness to agonist stimulation once occupancy by the inverse agonist is removed.…”

Section: Discussionmentioning

confidence: 99%

“…), constitutive receptor activity, like agonist-dependent activity, has also been shown to activate desensitization mechanisms. This receptor activity results in receptor systems that are "constitutively desensitized," as evidenced by constitutive receptor phosphorylation, internalization, and decreased responsiveness to agonist stimulation (Pei et al, 1994;Berg et al, 1999;Barak et al, 2003;Sullivan et al, 2015b). Prolonged reduction of constitutive receptor activity that activates desensitization mechanisms by treatment with inverse agonists allows receptor systems to resensitize, leading to increased responsiveness to agonists (Milligan and Bond, 1997;Berg et al, 1999;MisereyLenkei et al, 2002;Chanrion et al, 2008;Nijmeijer et al, 2010;Sullivan et al, 2015b).…”

Section: Introductionmentioning

confidence: 99%

See 1 more Smart Citation

Constitutive Desensitization of Opioid Receptors in Peripheral Sensory Neurons

Sullivan

Chavera

Jamshidi

et al. 2016

The Journal of Pharmacology and Experimental Therapeutics

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Opioid receptors expressed by peripheral pain-sensing neurons are functionally inactive for antinociceptive signaling under most basal conditions; however, tissue damage or exposure to inflammatory mediators (e.g., bradykinin) converts these receptors from a nonresponsive state to a functionally competent state. Here we tested the hypothesis that the basal, nonresponsive state of the mu-and delta-opioid receptors (MOR and DOR, respectively) is the result of constitutive receptor activity that activates desensitization mechanisms, resulting in MOR and DOR receptor systems that are constitutively desensitized. ]-enkephalin, inhibited prostaglandin E 2 (PGE 2 )-stimulated cAMP accumulation in peripheral sensory neurons in culture (ex vivo) or inhibited PGE 2 -stimulated thermal allodynia in the rat hind paw in vivo. Prolonged treatment with naloxone induced MOR and DOR responsiveness both in vivo and ex vivo to a similar magnitude as that produced by bradykinin. Also similar to bradykinin, the effect of naloxone persisted for 60 minutes after washout of the ligand. By contrast, prolonged treatment with 6b-naltrexol, did not induce functional competence of MOR or DOR but blocked the effect of naloxone. Treatment with siRNA for b-arrestin-2, but not b-arrestin-1, also induced MOR and DOR functional competence in cultured peripheral sensory neurons. These data suggest that the lack of responsiveness of MOR and DOR to agonist for antinociceptive signaling in peripheral sensory neurons is due to constitutive desensitization that is likely mediated by b-arrestin-2.

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Section: Discussionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

Constitutive Desensitization of Opioid Receptors in Peripheral Sensory Neurons

Sullivan

Chavera

Jamshidi

et al. 2016

The Journal of Pharmacology and Experimental Therapeutics

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“…clinically useful drugs previously characterized as antagonists, in fact, have inverse agonist properties when evaluated with appropriate test systems ( Bond and Ijzerman, 2006 ; Greasley and Clapham, 2006 ; Parra and Bond, 2007 ; Khilnani and Khilnani, 2011 ). For example, almost all of the atypical antipsychotic drugs previously thought to be antagonists have been shown to have inverse agonist activity at serotonin Type 2 receptors ( Herrick-Davis et al, 2000 ; Sullivan et al, 2015a ; Meltzer, 2017 ), reinforcing the notion that inverse agonism may be important for therapeutic efficacy of these drugs. It is important to note that for many diseases, especially for those that stem from disorders of the CNS (schizophrenia, affective disorders, autism, etc.…”

Section: Constitutive Activity and Inverse Agonismmentioning

confidence: 99%

Making Sense of Pharmacology: Inverse Agonism and Functional Selectivity

Berg¹,

Clarke²

2018

International Journal of Neuropsychopharmacology

126

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Constitutive receptor activity/inverse agonism and functional selectivity/biased agonism are 2 concepts in contemporary pharmacology that have major implications for the use of drugs in medicine and research as well as for the processes of new drug development. Traditional receptor theory postulated that receptors in a population are quiescent unless activated by a ligand. Within this framework ligands could act as agonists with various degrees of intrinsic efficacy, or as antagonists with zero intrinsic efficacy. We now know that receptors can be active without an activating ligand and thus display “constitutive” activity. As a result, a new class of ligand was discovered that can reduce the constitutive activity of a receptor. These ligands produce the opposite effect of an agonist and are called inverse agonists. The second topic discussed is functional selectivity, also commonly referred to as biased agonism. Traditional receptor theory also posited that intrinsic efficacy is a single drug property independent of the system in which the drug acts. However, we now know that a drug, acting at a single receptor subtype, can have multiple intrinsic efficacies that differ depending on which of the multiple responses coupled to a receptor is measured. Thus, a drug can be simultaneously an agonist, an antagonist, and an inverse agonist acting at the same receptor. This means that drugs have an additional level of selectivity (signaling selectivity or “functional selectivity”) beyond the traditional receptor selectivity. Both inverse agonism and functional selectivity need to be considered when drugs are used as medicines or as research tools.

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“…It is clear that is some brain regions and depending on state, native 5-HT2CR display constitutive activity which can vary largely (Di Giovanni et al 1999;Di Matteo et al 2000;Gobert et al 2000;Leggio et al 2009;Navailles et al 2004;2013a;2013b). A number of antipsychotics behave actually as inverse agonists (Berg et al 1999;Herrick-Davis et al 2000;Rauser et al 2001;Navailles et al, 2004;Aloyo et al 2009;Sullivan et al; and if the 5-HT2CR is a target, their effectiveness may depend on the level of constitute activity of the receptor (Navailles et al 2013b). A complicating factor is that constitutive activity may vary with transduction pathway (Berg et al 1994;1998a;1998b;2001;2008a;2008b;Moya et al 2007;Wang et al 2000;Werry et al 2005;2008;Berg and Clarke 2009), receptor desensitization and trafficking may be at play as well Marion et al, 2004) and different ligands may possess different pathway selectivity.…”

Section: Rna Editing Spinal Cord Injury and More: A Case For Inversementioning

confidence: 99%