2,3-Dihydro-dithiin and -dithiepine-1,1,4,4-tetroxides: small molecule non-peptide antagonists of the human galanin hGAL-1 receptor

Scott, Mark J.; Ross, Tina Morgan; Lee, Daniel H. S.; Wang, Hoau-Yan; Shank, Richard P.; Wild, Kenneth D.; Davis, Coralie B.; Crooke, Jeffrey J.; Potocki, Alexander C; Reitz, Allen B.

doi:10.1016/s0968-0896(00)00062-6

Cited by 59 publications

(27 citation statements)

References 47 publications

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“…Treatment of dispersed DRG neurons with the nonpeptide GAL 1 -specific antagonist RWJ-57408 (Scott et al, 2000) failed to suppress neurite outgrowth (Mahoney et al, 2003a). Consistent with this, GAL 1 -KO mice have no reduction in regenerative capacity after a nerve crush injury (Blakeman et al, 2003) nor a deficit in neuritogenesis in vitro (Mahoney et al, 2003a).…”

Section: Regeneration and Neurite Outgrowthmentioning

confidence: 65%

“…The antifungal metabolite Sch202596 (spirocoumaron) was described in 1997 as the first nonpeptide galanin-receptor ligand with antagonist activity in micromolar concentrations at membranes of human Bowes melanoma cells (Chu et al, 1997), which endogenously express GAL 1 and GAL 3 (Lang et al, 2001). In the same cell line, the compound RWJ-57408 (2,3-dihydro-2-(4-methylphenyl)-1,4-dithiepine-1,1,4,4-tetroxide) was shown to be an antagonist with submicromolar affinity (Scott et al, 2000). The antagonistic properties of RWJ-57408 have been confirmed in cultured rat myenteric neurons (Anselmi et al, 2009).…”

Section: Galanin Receptor-ligand Interactionsmentioning

confidence: 99%

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Physiology, Signaling, and Pharmacology of Galanin Peptides and Receptors: Three Decades of Emerging Diversity

et al. 2014

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Section: Regeneration and Neurite Outgrowthmentioning

confidence: 65%

Section: Galanin Receptor-ligand Interactionsmentioning

confidence: 99%

Physiology, Signaling, and Pharmacology of Galanin Peptides and Receptors: Three Decades of Emerging Diversity

et al. 2014

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“…GAL-R1 exerts it physiological actions in these regions via the activation of G i / 0 G-proteins, leading to inhibition of adenylyl cyclase and cAMP, and closure of voltage-sensitive calcium channels. Differentiating the functional roles of galanin receptor subtypes has been limited by the absence of subtype selective, high-affinity, soluble galanin receptor agonists and antagonists (Scott et al, 2000;Saar et al, 2002).…”

Section: Introductionmentioning

confidence: 99%

Galanin GAL-R1 Receptor Null Mutant Mice Display Increased Anxiety-Like Behavior Specific to the Elevated Plus-Maze

Holmes

Kinney

Wrenn

et al. 2003

Neuropsychopharmacol

189

137

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The neuropeptide galanin coexists with norepinephrine and serotonin in neural systems mediating emotion. Previous findings suggested that galanin modulates anxiety-related behaviors in rodents. Three galanin receptor subtypes have been cloned; however, understanding their functions has been limited by the lack of galanin receptor subtype-selective ligands. To study the role of the galanin GAL-R1 receptor subtype in mediating anxiety-related behavior, we generated mice with a null mutation in the Galr1 gene. GAL-R1 À/À are viable and show no abnormalities in health, neurological reflexes, motoric functions, or sensory abilities. On a battery of tests for anxietylike behavior, GAL-R1 À/À showed increased anxiety-like behavior on the elevated plus-maze test. Anxiety-related behaviors on the light/dark exploration, emergence, and open field tests were normal in GAL-R1 À/À. This test-specific anxiety-like phenotype was confirmed in a second, independent cohort of GAL-R1 null mutant mice and +/+ controls. Principal components factor analysis of behavioral scores from 279 mice suggested that anxiety-like behavior on the elevated plus-maze was qualitatively distinct from behavior on other tests in the battery. In addition, exposure to the elevated plus-maze produced a significantly greater neuroendocrine response than exposure to the light/dark exploration test, as analyzed in normal C57BL/6J mice. These behavioral findings in the first galanin receptor null mutant mouse are consistent with the hypothesis that galanin exerts anxiolytic actions via the GAL-R1 receptor under conditions of relatively high stress.

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“…An antagonist (RWJ-57408) selective for the GAL1 receptor (Mahoney et al 2003;Scott et al 2000) was applied in advance of the application of GAL (1 M) at concentrations (1-10 M) shown previously to be effective in blocking GAL action elsewhere (Mahoney et al 2003;Scott et al 2000). As can be seen in Fig.…”

Section: Galanin Decreases Excitatory Neurotransmissionmentioning

confidence: 99%

“…While three different receptor subtypes for GAL have been identified, progress in the development of receptor-specific antagonists has been slow (Xu et al 2005). Nonetheless, a potential GAL1R antagonist has been described (Mahoney et al 2003;Scott et al 2000), but it was ineffective in blocking GAL presynaptic inhibition in SON. Thus it is likely that either GAL2 or GAL3 receptors mediate these effects.…”

Section: Galanin Presynaptically Reduces Excitatory Neurotransmissionmentioning

confidence: 99%

Galanin Modulates Neuronal and Synaptic Properties in the Rat Supraoptic Nucleus in a Use and State Dependent Manner

Kozoriz

Kuzmiski²,

Hirasawa³

et al. 2006

Journal of Neurophysiology

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. Galanin modulates neuronal and synaptic properties in the rat supraoptic nucleus in a use and state dependent manner. J Neurophysiol 96: 154 -164, 2006; doi:10.1152/jn.01028.2005. The magnocellular neurons of the hypothalamic supraoptic nucleus (SON) synthesize and secrete oxytocin (OXT) and vasopressin (AVP) from their dendrites. These peptides, and several other neurotransmitters, have been shown to modulate afferent glutamatergic neurotransmission in the SON. The neuropeptide, galanin (GAL) is also localized in SON magnocellular neurons and in afferent fibers in the nucleus. We show that GAL dose-dependently reduces evoked excitatory postsynaptic currents (eEPSCs), alters paired pulse ratio and decreases mEPSC frequency, but not amplitude or decay kinetics in both OXT and AVP neurons. GAL therefore modulates excitatory neurotransmission at a likely presynaptic receptor. Neither OXT/AVP, GABA B nor cannabinoid antagonists blocked this effect. A GAL2/3 agonist mimicked GAL's action while GAL1 antagonist did not block GAL's effect, suggesting that GAL2/3 receptors mediate the presynaptic effect. In nondehydrated rats GAL causes a small postsynaptic response, as assessed by input resistance measurements. When the rats were water deprived for 2 days the presynaptic response to GAL was unaltered; however, the postsynaptic decrease in input resistance and hyperpolarization was increased, an effect consistent with a previously described increase in GAL1 receptor expression in dehydration. A GAL1 receptor antagonist blocked the postsynaptic effects. Last, when a train of eEPSCs was elicited, GAL was found to inhibit the earlier events in a train but not the latter. This indicates that GAL may modulate a single synaptic event more effectively than trains of synaptic inputs, thereby acting as a high-pass filter.

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2,3-Dihydro-dithiin and -dithiepine-1,1,4,4-tetroxides: small molecule non-peptide antagonists of the human galanin hGAL-1 receptor

Cited by 59 publications

References 47 publications

Physiology, Signaling, and Pharmacology of Galanin Peptides and Receptors: Three Decades of Emerging Diversity

Physiology, Signaling, and Pharmacology of Galanin Peptides and Receptors: Three Decades of Emerging Diversity

Galanin GAL-R1 Receptor Null Mutant Mice Display Increased Anxiety-Like Behavior Specific to the Elevated Plus-Maze

Galanin Modulates Neuronal and Synaptic Properties in the Rat Supraoptic Nucleus in a Use and State Dependent Manner

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