SGS742: the first GABAB receptor antagonist in clinical trials

Froestl, Wolfgang; Gallagher, Michela; Jenkins, Helen; Madrid, Annette; Melcher, Thorsten; Teichman, Sam L.; Mondadori, Cesare; Pearlman, Rodney

doi:10.1016/j.bcp.2004.07.030

Cited by 173 publications

(133 citation statements)

References 21 publications

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“…In a Phase II doubleblind, placebo-controlled study in 110 patients characterized by mild cognitive deficits, repeated administration of SGS742 significantly improved attention and working memory. 69 These clinical findings are supported by preclinical studies showing that the GABA B receptor antagonist displays pronounced cognitive enhancing effects in rats involved in different learning tasks. 70 These behavioral observations are paralleled by molecular experiments revealing that SGS742 significantly increased BDNF expression in frontal cortex and hippocampus.…”

Section: Gaba-b Antagonistsmentioning

confidence: 81%

“…Among the drugs that are currently being tested in clinical trials for AD, Froestl et al 69 have illustrated the potential of the GABA B receptor antagonist SGS742. In a Phase II doubleblind, placebo-controlled study in 110 patients characterized by mild cognitive deficits, repeated administration of SGS742 significantly improved attention and working memory.…”

Section: Gaba-b Antagonistsmentioning

confidence: 99%

“…Based on these preliminary preclinical and clinical observations, a second Phase II clinical trial in 280 AD patients is underway. 69 …”

Section: Gaba-b Antagonistsmentioning

confidence: 99%

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The expanding role of BDNF: a therapeutic target for Alzheimer's disease?

2005

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Finding an effective treatment for chronic neurodegenerative disorders still represents an unmet goal. There is considerable evidence that such disorders represent a combination of genetic determinants and failure of neuroprotective mechanisms sparking a wider degree of interest in shedding light on the cellular changes responsible for these devastating disorders. Because of their role in survival or differentiation of developing neurons, as well as the recent discovery of their importance in regulating synaptic plasticity during adulthood, neurotrophic factors have been suggested as essential contributors of the etiology of neurodegenerative disorders. Alzheimer's disease (AD) is a complex, chronic, devastating disease that affects a high percentage of the population over 65 years of age. This review will focus on different pharmacological interventions that are currently in use or drugs under development, narrowing the therapeutic agents to those that interfere with the expression of the trophic factor brain-derived neurotrophic factor (BDNF), a molecule playing a pivotal role in synaptic plasticity and cognition. From these findings, it appears clear that BDNF is implicated in the mechanism of action of drugs that improve cognitive deficits in animal models of AD and in AD patients.

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Section: Gaba-b Antagonistsmentioning

confidence: 81%

Section: Gaba-b Antagonistsmentioning

confidence: 99%

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The expanding role of BDNF: a therapeutic target for Alzheimer's disease?

2005

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“…[141][142][143] Indeed, GABA B antagonists enhance the influence of SSRIs on serotonergic transmission in the frontal cortex. 87,144,145 …”

Section: Hybrid Monoaminergic/nonmonoaminergic Antidepressantsmentioning

confidence: 99%

Dual- and Triple-Acting Agents for Treating Core and Co-morbid Symptoms of Major Depression: Novel Concepts, New Drugs

Millan¹

2009

Neurotherapeutics

179

123

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Summary:The past decade of efforts to find improved treatment for major depression has been dominated by genomedriven programs of rational drug discovery directed toward highly selective ligands for nonmonoaminergic agents. Selective drugs may prove beneficial for specific symptoms, for certain patient subpopulations, or both. However, network analyses of the brain and its dysfunction suggest that agents with multiple and complementary modes of action are more likely to show broad-based efficacy against core and comorbid symptoms of depression. Strategies for improved multitarget exploitation of monoaminergic mechanisms include triple inhibitors of dopamine, serotonin (5-HT) and noradrenaline reuptake, and drugs interfering with feedback actions of monoamines at inhibitory 5-HT 1A , 5-HT 1B and possibly 5-HT 5A and 5-HT 7 receptors. Specific subsets of postsynaptic 5-HT receptors mediating antidepressant actions are under study (e.g., 5-HT 4 and 5-HT 6 ). Association of a clinically characterized antidepressant mechanism with a nonmonoaminergic component of activity is an attractive strategy. For example, agomelatine (a melatonin agonist/5-HT 2C antagonist) has clinically proven activity in major depression. Dual neurokinin 1 antagonists/5-HT reuptake inhibitors (SRIs) and melanocortin 4 antagonists/SRIs should display advantages over their selective counterparts, and histamine H 3 antagonists/SRIs, GABA B antagonists/SRIs, glutamatergic/SRIs, and cholinergic agents/SRIs may counter the compromised cognitive function of depression. Finally, drugs that suppress 5-HT reuptake and blunt hypothalamo-pituitary-adrenocorticotrophic axis overdrive, or that act at intracellular proteins such as GSK-3␤, may abrogate the negative effects of chronic stress on mood and neuronal integrity. This review discusses the discovery and development of dual-and tripleacting antidepressants, focusing on novel concepts and new drugs disclosed over the last 2 to 3 years.

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“…CGP36742 or SGS742 reached phase II clinical trials, enhancing memory in mildly memory-impaired subjects. 18 However, because CGP36742 (SGS742) is approximately equipotent on GABA B as it is on GABA C receptors, it is not clear whether the pharmacological effects of CGP36742 are due to its GABA B or GABA C activity. In continuation of our efforts to identify the role of GABA C receptors in the CNS, we discovered that the selective GABA C receptor antagonists, cis-and trans-(3-aminocyclopentanyl)-n-butylphosphinic acid (cis-3-ACPBPA 4 and trans-3-ACPBPA 5; Figure 1), inhibit myopia progression in chicks and facilitate learning and memory in the Morris Water Maze task in rats.…”

mentioning

confidence: 99%

Novel Cyclic Phosphinic Acids as GABA_C ρ Receptor Antagonists: Design, Synthesis, and Pharmacology

Gavande

Yamamoto

Salam

et al. 2010

ACS Med. Chem. Lett.

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Understanding the role of GABA C receptors in the central nervous system is limited due to a lack of specific ligands. Novel γ-aminobutyric acid (GABA) analogues based on 3-(aminomethyl)-1-oxo-1-hydroxy-phospholane 17 and 3-(guanido)-1-oxo-1-hydroxy-phospholane 19 were investigated to obtain selective GABA C receptor antagonists. A compound of high potency (19, K B =10 μM) and selectivity (greater than 100 times at F 1 GABA C receptors as compared to R 1 β 2 γ 2L GABA A and GABA B(1b,2) receptors) was obtained. The cyclic phosphinic acids (17 and 19) are novel lead agents for developing into more potent and selective GABA C receptor antagonists with increased lipophilicity for future in vivo studies.

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SGS742: the first GABAB receptor antagonist in clinical trials

Cited by 173 publications

References 21 publications

The expanding role of BDNF: a therapeutic target for Alzheimer's disease?

The expanding role of BDNF: a therapeutic target for Alzheimer's disease?

Dual- and Triple-Acting Agents for Treating Core and Co-morbid Symptoms of Major Depression: Novel Concepts, New Drugs

Novel Cyclic Phosphinic Acids as GABA_C ρ Receptor Antagonists: Design, Synthesis, and Pharmacology

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SGS742: the first GABAB receptor antagonist in clinical trials

Cited by 173 publications

References 21 publications

The expanding role of BDNF: a therapeutic target for Alzheimer's disease?

The expanding role of BDNF: a therapeutic target for Alzheimer's disease?

Dual- and Triple-Acting Agents for Treating Core and Co-morbid Symptoms of Major Depression: Novel Concepts, New Drugs

Novel Cyclic Phosphinic Acids as GABAC ρ Receptor Antagonists: Design, Synthesis, and Pharmacology

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Novel Cyclic Phosphinic Acids as GABA_C ρ Receptor Antagonists: Design, Synthesis, and Pharmacology