Flesinoxan treatment of Generalized Anxiety Disorder: A fixed dose, placebo-controlled trial

Noël, F.; Stevens, Gary; Bradford, Daniel

doi:10.1016/0924-977x(96)83134-8

Cited by 4 publications

(2 citation statements)

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“…For example, the partial agonists buspirone and tandospirone are clinically employed anxiolytics [8,11]. The antidepressant effects of 5-HT 1A receptor agonists [12][13][14] have been explored with flesinoxan [15,16] and with flibanserin, which also counters female sexual dysfunction [17,18]. 5-HT 1A receptor agonism is also a prominent feature of several anti-Parkinson's disease drugs, including bromocriptine, lisuride and pardoprunox (SLV308) [19][20][21].…”

Section: Review Newman-tancredimentioning

confidence: 99%

Biased agonism at serotonin 5-HT_1Areceptors: preferential postsynaptic activity for improved therapy of CNS disorders

Newman‐Tancredi¹

2011

Neuropsychiatry

106

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Practice pointsSerotonin or 5-hydroxytryptamine (5-HT) 1A receptors are attractive targets for pharmacotherapy of pathologies associated with dysfunctional serotonergic neurotransmission, including anxiety, depression, Parkinson's disease, pain and schizophrenia. 5-HT 1A receptors are expressed both as presynaptic autoreceptors on serotonergic cell bodies in the raphe and as postsynaptic heteroreceptors in multiple brain regions including the cortex, hippocampus, septum and hypothalamus.The signaling cascades elicited by 5-HT 1A receptor activation differ between brain regions: different G-protein subtypes, different second messengers and different neurochemical read-outs.The concept of 'biased agonism' or 'functional selectivity' asserts that agonists can preferentially direct receptor signaling to specific intracellular responses. This opens the possibility of targeting receptors in specific cellular environments or brain regions.F15599 is a selective 5-HT 1A receptor agonist that exhibits biased agonism, preferentially activating Gai versus Gao G-protein subtypes. F15599 preferentially activates ERK1/2 phosphorylation more than G-protein, receptor internalization or adenylyl cyclase inhibition.F15599 stimulates rat medial prefrontal cortex pyramidal neuron electrical activity and dopamine release (controlled by postsynaptic 5-HT 1A receptors) at low doses that do not inhibit raphe serotonergic neuron electrical activity or hippocampal 5-HT release (controlled by presynaptic 5-HT 1A receptors).F15599 preferentially stimulates c-Fos expression and ERK1/2 phosphorylation in rat prefrontal cortex, with less pronounced effects in the raphe. This preferential postsynaptic activity is not observed with other 5-HT 1A agonists.In rats F15599 exhibits potent antidepressant-like activity in the forced swim test, inhibits stress-induced ultrasonic vocalization and attenuates phencyclidine-induced cognitive impairments in reversal learning, in novel object recognition and in a hole-board test.At 'antidepressant' doses in rats, F15599 does not induce serotonin syndrome, does not disrupt attentional performance, does not impair working memory and does not inhibit prepulse inhibition of startle response.For reprint orders, please contact: reprints@futuremedicine.com

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Section: Review Newman-tancredimentioning

confidence: 99%

Biased agonism at serotonin 5-HT_1Areceptors: preferential postsynaptic activity for improved therapy of CNS disorders

Newman‐Tancredi¹

2011

Neuropsychiatry

106

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“…These drugs (buspirone, tandospirone, ipsapirone, and flesinoxan) are effective in both GAD and CC (Chessick, Allen, Thase, Batista Miralha da Cunha, Kapczinski, de Lima et al, 2006;Cutler, Sramek, Keppel Hesselink, Krol, Roeschen, Rickels et al, 1993;Fricchione, 2004;Li, Inoue, Hashimoto, & Koyama, 2001;Nishikawa, Inoue, Masui, Izumi, & Koyama, 2007;Nishitsuji, To, Murakami, Kodama, Kobayashi, Yamada et al, 2004;Noel, Stevens, & Bradford, 1996).…”

Section: Predictive Validitymentioning

confidence: 99%

Contextual conditioning in rats as an animal model for generalized anxiety disorder

Luyten

Vansteenwegen

Kuyck

et al. 2011

Cogn Affect Behav Neurosci

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Animal models of psychiatric disorders are important translational tools for exploring new treatment options and gaining more insight into the disease. Thus far, there is no systematically validated animal model for generalized anxiety disorder (GAD), a severely impairing and difficult-to-treat disease. In this review, we propose contextual conditioning (CC) as an animal model for GAD. We argue that this model has sufficient face validity (there are several symptom similarities), predictive validity (it responds to clinically effective treatments), and construct validity (the underlying mechanisms are comparable). Although the refinement and validation of an animal model is a never-ending process, we want to give a concise overview of the currently available evidence. We suggest that the CC model might be a valuable preclinical tool to enhance the development of new treatment strategies and our understanding of GAD.

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Effects of 5-HT1A receptor ligands in a modified Geller-Seifter conflict model in the rat

King

Gommans

Joordens

et al. 1997

European Journal of Pharmacology

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Flesinoxan treatment of Generalized Anxiety Disorder: A fixed dose, placebo-controlled trial

Cited by 4 publications

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Biased agonism at serotonin 5-HT_1Areceptors: preferential postsynaptic activity for improved therapy of CNS disorders

Biased agonism at serotonin 5-HT_1Areceptors: preferential postsynaptic activity for improved therapy of CNS disorders

Contextual conditioning in rats as an animal model for generalized anxiety disorder

Effects of 5-HT1A receptor ligands in a modified Geller-Seifter conflict model in the rat

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Flesinoxan treatment of Generalized Anxiety Disorder: A fixed dose, placebo-controlled trial

Cited by 4 publications

References 0 publications

Biased agonism at serotonin 5-HT1Areceptors: preferential postsynaptic activity for improved therapy of CNS disorders

Biased agonism at serotonin 5-HT1Areceptors: preferential postsynaptic activity for improved therapy of CNS disorders

Contextual conditioning in rats as an animal model for generalized anxiety disorder

Effects of 5-HT1A receptor ligands in a modified Geller-Seifter conflict model in the rat

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Biased agonism at serotonin 5-HT_1Areceptors: preferential postsynaptic activity for improved therapy of CNS disorders

Biased agonism at serotonin 5-HT_1Areceptors: preferential postsynaptic activity for improved therapy of CNS disorders