Antagonist Functional Selectivity: 5-HT2A Serotonin Receptor Antagonists Differentially Regulate 5-HT2A Receptor Protein Level In Vivo

Yadav, Prem N.; Kroeze, Wesley K.; Farrell, Martilias S.; Roth, Bryan L.

doi:10.1124/jpet.111.183780

Cited by 78 publications

(64 citation statements)

References 36 publications

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“…Moreover, no significant interaction between the two factors was detected in these brain regions (Table 1). which contributes to the therapeutic efficacy of these SGAs (Kusumi et al, 2000, Tarazi et al, 2002, Huang et al, 2006a, Kuroki et al, 2008, Yadav et al, 2011. Consistent with these reports, this study found that olanzapine only treatment decreased 5-HT 2A R bindings in brain regions involved in antipsychotic therapeutics including the PFC, Cg, NAcC and NAcS (Tarazi et al, 2002, Cohen et al, 2003, Stahl, 2003, Yadav et al, 2011.…”

Section: Examples Of [³H]paroxetine Binding To 5-htt Are Presented Insupporting

confidence: 79%

Effects of olanzapine and betahistine co-treatment on serotonin transporter, 5-HT2A and dopamine D2 receptor binding density

Lian

Huang

Pai

et al. 2013

Progress in Neuro-Psychopharmacology and Biological Psychiatry

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. 2013, 'Effects of olanzapine and betahistine co-treatment on serotonin transporter, 5-HT2A and dopamine D2 receptor binding density ', vol. 47, Effects of olanzapine and betahistine co-treatment on serotonin transporter, 5-HT2A and dopamine D2 receptor binding density AbstractOlanzapine is widely used in treating multiple domains of schizophrenia symptoms but induces serious metabolic side-effects. Recent evidence has showed that co-treatment of betahistine (a histaminergic H1 receptor agonist and H3 receptor antagonist) is effective for preventing olanzapine-induced weight gain/ obesity, however it is not clear whether this co-treatment affects on the primary therapeutic receptor binding sites of olanzapine such as serotonergic 5-HT2A receptors (5-HT2AR) and dopaminergic D2 receptors (D2R). Therefore, this study investigated the effects of this co-treatment on 5-HT2AR, 5-HT transporter

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Section: Examples Of [³H]paroxetine Binding To 5-htt Are Presented Insupporting

confidence: 79%

Effects of olanzapine and betahistine co-treatment on serotonin transporter, 5-HT2A and dopamine D2 receptor binding density

Lian

Huang

Pai

et al. 2013

Progress in Neuro-Psychopharmacology and Biological Psychiatry

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“…The bias plot highlights the differences in potency and efficacy values for each ligand in both G protein and arrestin pathways. For example, we have identified 5-HT 2A inverse agonists which can induce receptor internalization and downregulation in vitro and in vivo without activating either G protein signaling or arrestin translocation (Bhatnagar et al, 2001;Xia et al, 2003;Yadav et al, 2011). In future studies, it will be useful to combine in vivo behavioral studies and a global study of intracellular signaling with functionally selective ligands, to fully understand which signaling cascades contribute to the various behavioral effects of KOR agonism.…”

Section: Discussionmentioning

confidence: 99%

Identification of Novel Functionally Selective κ-Opioid Receptor Scaffolds

White

Scopton

Rives

et al. 2014

Molecular Pharmacology

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121

116

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The k-opioid receptor (KOR)-dynorphin system has been implicated in the control of affect, cognition, and motivation, and is thought to be dysregulated in mood and psychotic disorders, as well as in various phases of opioid dependence. KOR agonists exhibit analgesic effects, although the adverse effects produced by some KOR agonists, including sedation, dysphoria, and hallucinations, have limited their clinical use. Interestingly, KOR-mediated dysphoria, assessed in rodents as aversion, has recently been attributed to the activation of the p38 mitogen-activated protein kinase pathway following arrestin recruitment to the activated KOR. Therefore, KOR-selective G protein-biased agonists, which do not recruit arrestin, have been proposed to be more effective analgesics, without the adverse effects triggered by the arrestin pathway. As an initial step toward identifying novel biased KOR agonists, we applied a multifaceted screening strategy utilizing both in silico and parallel screening approaches. We identified several KORselective ligand scaffolds with a range of signaling bias in vitro. The arylacetamide-based scaffold includes both G protein-and b-arrestin-biased ligands, while the endogenous peptides and the diterpene scaffolds are G protein biased. Interestingly, we found scaffold screening to be more successful than library screening in identifying biased ligands. Many of the identified functionally selective ligands are potent selective KOR agonists that are reported to be active in the central nervous system. They therefore represent excellent candidates for in vivo studies aiming at determining the behavioral effects mediated by specific KORmediated signaling cascades.

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“…One thing that is unclear, however, is the degree of inverse agonism required for therapeutic efficacy in psychosis and related disorders (76), and future studies examining drugs with a range of antagonist functional selectivity and inverse agonism will be needed to address this point. Finally, additional extensive research is needed to establish the range of disorders in which 5-HT 2A inverse agonists can substitute for or augment subeffective doses of APDs.…”

Section: Discussionmentioning

confidence: 99%

Lorcaserin and pimavanserin: emerging selectivity of serotonin receptor subtype–targeted drugs

Meltzer¹,

Roth²

2013

J. Clin. Invest.

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103

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Serotonin (5-hydroxytryptamine, or 5-HT) receptors mediate a plethora of physiological phenomena in the brain and the periphery. Additionally, serotonergic dysfunction has been implicated in nearly every neuropsychiatric disorder. The effects of serotonin are mediated by fourteen GPCRs. Both the therapeutic actions and side effects of commonly prescribed drugs are frequently due to nonspecific actions on various 5-HT receptor subtypes. For more than 20 years, the search for clinically efficacious drugs that selectively target 5-HT receptor subtypes has been only occasionally successful. This review provides an overview of 5-HT receptor pharmacology and discusses two recent 5-HT receptor subtype-selective drugs, lorcaserin and pimavanserin, which target the 5HT 2C and 5HT 2A receptors and provide new treatments for obesity and Parkinson's disease psychosis, respectively. Serotonin receptors and signal transductionSerotonin, which was known to be the principal vasoconstricting substance found in serum, was chemically identified as 5-hydroxytryptamine by Rapport and colleagues in 1948 (1). Although the effects of serotonin on smooth muscle and other peripheral organs were long appreciated, it wasn't until its structural similarity to lysergic acid diethylamide (LSD) was noted that serotonin and its receptors were linked to neurotransmission (2). Distinct serotonin receptor subtypes were proposed in 1957 (3), with the 5-HT1 receptors having high affinity for serotonin and the 5-HT2 receptors having relatively low affinity for 5-HT. The so-called 5-HT1 and 5-HT2 receptors identified pharmacologically by Gaddum and colleagues (3) roughly correspond to what are now known as the 5-HT 1 and 5-HT 2 families of receptors ( Figure 1).With the development of radioligand-binding technology, multiple distinct serotonin receptors were identified based principally on their differential radioligand-binding properties. Following the cloning of the β-adrenergic receptor (4), 5-HT 1A (5), the first socalled orphan GPCR, was cloned by Brian Kobilka in collaboration with Marc Caron and others (6, 7). In rapid succession, the large family of G protein-coupled serotonin receptors we now appreciate were identified by molecular cloning technology and characterized by pharmacological and biochemical studies (8, 9), including 5-HT 1B/1D (10) and 5-HT 1E (11), as well as 5-HT 2A (12, 13) and 5-HT 2C (14, 15), which have lower affinities for 5-HT than the other serotonin receptors. The 5-HT 4 receptor was also one of the early 5-HT receptor subtypes identified mainly by radioligand binding and pharmacological studies (refs. 16, 17, and see Figure 1).In terms of signal transduction and pharmacology, we now know that all members of the 5-HT 1 family are intronless and couple to the Gi family of heterotrimeric G proteins -in keeping with the original description of the 5-HT 1A receptor (7). The 5-HT 1 family of receptors has been successfully exploited for the treatment of anxiety and depression with the development of drugs like buspirone (Tabl...

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Antagonist Functional Selectivity: 5-HT2A Serotonin Receptor Antagonists Differentially Regulate 5-HT2A Receptor Protein Level In Vivo

Cited by 78 publications

References 36 publications

Effects of olanzapine and betahistine co-treatment on serotonin transporter, 5-HT2A and dopamine D2 receptor binding density

Effects of olanzapine and betahistine co-treatment on serotonin transporter, 5-HT2A and dopamine D2 receptor binding density

Identification of Novel Functionally Selective κ-Opioid Receptor Scaffolds

Lorcaserin and pimavanserin: emerging selectivity of serotonin receptor subtype–targeted drugs

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