Galmic, a nonpeptide galanin receptor agonist, affects behaviors in seizure, pain, and forced-swim tests

Bartfai, Tamás; Lü, Xiaoying; Badie-Mahdavi, H.; Barr, Alasdair M.; Mazarati, Andréy; Hua, Xiao‐Ying; Yaksh, Tony L.; Haberhauer, Gebhard; Ceide, Susana Conde; Trembleau, Laurent; Somogyi, László; Kröck, Lenz; Rebek, Julius

doi:10.1073/pnas.0403802101

Cited by 134 publications

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“…Two systemically active nonpeptide galanin receptor agonists, Galnon and Galmic, from the Langel and Rebek groups (17,29), became important pharmacological tools for studying the pharmacology of galanin signaling and represented prototypic compounds for design of improved nonpeptide ligands. Peptide analogues shorter than the endogenous galanin with receptor subtype selectivity were synthesized and characterized (36,44,45).…”

Section: Discussionmentioning

confidence: 99%

“…Ligand competition binding of 125 I porcine galanin to the membrane preparations (29) was performed in a volume of 150 μL in a 96-well plate. Cell membranes were diluted in Hepes buffer containing 25 mM Hepes, pH 7.4, 10 mM MgCl 2 , 1 mM CaCl 2 , 0.5% BSA, and 1× protease inhibitor.…”

Section: Methodsmentioning

confidence: 99%

“…Much effort has been made in recent years toward development of systemically active agonists/ modulators for GalR1 and GalR2 receptors and, as of today, two nonpeptide, systemically active agonists, Galnon (17) and Galmic (29), and a CNSpenetrating peptide, galanin analogue Gal-B2 (30)(31)(32)(33), have been synthesized and characterized. All three galanin receptor agonists have been shown to exhibit potent anticonvulsant effect upon systemic application.…”

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confidence: 99%

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GalR2-positive allosteric modulator exhibits anticonvulsant effects in animal models

Lü

Roberts

Xia

et al. 2010

Proc. Natl. Acad. Sci. U.S.A.

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Galanin receptors type 1 (GalR1) and/or type 2 (GalR2) represent unique pharmacological targets for treatment of seizures and epilepsy. Previous studies have shown that the endogenous peptide ligand galanin exerts powerful anticonvulsant effect through activation of these two G protein-coupled receptors, which are highly expressed in the temporal lobe of rodent brain. Here we report the characterization of a putative GalR2-positive allosteric modulator CYM2503. CYM2503 potentiated the galanin-stimulated IP1 accumulation in HEK293 cells stably expressing GalR2 receptor, whereas it exhibited no detectable affinity for the 125 I galanin-binding site of GalR2 receptor, an effect consistent with that of a positive allosteric modulator. In the rat Li-pilocarpine status epilepticus model, CYM2503, injected intraperitoneally, increased the latency to first electrographic seizure and the latency to first stage 3 behavioral seizure, decreased the latency to the establishment of status epilepticus, and dramatically decreased the mortality. In a Li-pilocarpine seizure model in mice, CYM2503 increased the latency to first electrographic seizure and decreased the total time in seizure. CYM-2503 also attenuated electroshock-induced seizures in mice. Thus, CYM2503 provides a starting point for the development of anticonvulsant therapy using the galanin R2 receptor as target.galanin | seizure | G protein-coupled receptor | status epilepticus T he neuropeptide galanin (1) is widely expressed in the central nervous system (2-4), in which it regulates a variety of physiological and pathological processes, including pain, learning and memory, mood, addiction, and food intake (5-16). In addition, converging lines of evidence suggest a critical role for galanin in seizure control. Galanin has been shown to exhibit potent anticonvulsant effect in both acute and chronic seizure models in rodents. Intrahippocampally injected galanin strongly and irreversibly attenuated the status epilepticus (SE) induced by perforant path stimulation in rats (17). Mice with null mutation of galanin were more susceptible to develop SE after perforant path stimulation or systemic kainic acid injection, and exhibited more severe seizures following pentylenetetrazol injection (18). In contrast, mice that overexpress galanin under a dopamine-β-hydroxylase promoter had increased resistance to seizure induction in these three models (18). A separate line of transgenic mice that overexpress galanin under the plateletderived growth factor β promoter was found to exhibit delayed epileptogenesis induced by kindling stimulations (19). Moreover, galanin delivered to the rat brain via adenoassociated viral vectors has been shown to suppress kainic acid-induced seizures (20, 21), attenuate inferior collicular stimulation induced wild running seizure (21), and delay kindling development (22).The aforementioned anticonvulsant effects of galanin were most likely mediated through galanin receptor type 1 (GalR1) and type 2 (GalR2). GalR1-knockout mice exhibited spontaneous ...

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Section: Discussionmentioning

confidence: 99%

Section: Methodsmentioning

confidence: 99%

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confidence: 99%

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GalR2-positive allosteric modulator exhibits anticonvulsant effects in animal models

Lü

Roberts

Xia

et al. 2010

Proc. Natl. Acad. Sci. U.S.A.

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“…In addition, in vivo experiments in rats showed that galmic penetrates the blood-brain barrier quickly and exhibits agonist-like properties that mimic the galanin neuropeptide (22). No such properties were found for cyclodiastereomer 25.…”

Section: Resultsmentioning

confidence: 99%

“…In this study, we report an example of a nonpeptide subtype selective agonist for the galanin receptor, galmic, discovered by application of a combinatorial library approach (22).…”

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Synthesis of galmic: A nonpeptide galanin receptor agonist

Ceide

Trembleau²,

Haberhauer³

et al. 2004

Proc. Natl. Acad. Sci. U.S.A.

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Galanin is a neuropeptide with a wide variety of biological functions. Few nonpeptide ligands, capable of activating galanin receptors, are available today. Based on known pharmacophores of galanin and the tripeptidomimetic galnon, a combinatorial library was formulated, synthesized, and screened against the galanin receptor. An active compound, galmic, was identified and tested in vitro and in vivo for its affinity and efficacy at galanin receptors. The present work describes the total synthesis of galmic, the synthesis of its oxazole precursors, the coupling of the building blocks into a linear trimer, and the macrolactamization reaction.galnon ͉ mimetic G alanin is a 29-aa-long (30 aa in humans) neuroendocrine peptide, whose physiological functions are regulated by G protein-coupled receptors. Galanin is found throughout the central and peripheral nervous systems and the gastrointestinal tract (1-4). The effects of this peptide include inhibition of insulin release (5-7), inhibition of neurotransmiters involved in regulation and memory acquisition (8), modulation of food intake (9, 10) and sexual behavior (11), as well as effects on controlling pain threshold (12, 13) and in the pathogenesis of Alzheimer's disease (14).Studies involving L-Ala-substituted analogues of galanin have identified Trp-2, Asn-5, and Tyr-9 as well as the N-terminal amino group as being critical determinants for receptor binding. These amino acids are located in the N-terminal helical part of galanin that it is made up of the same 15 aa in all species from which it was isolated (15, 16). Fragments of galanin have shown low binding affinity but these peptides are vulnerable to the action of the peptidases and unable to cross the blood-brain barrier (17,18). Two nonpeptide antagonists of the galanin receptor have been reported, spirocoumaranon (Sch202596) (19) and 2,3-dihydro-2-(4-methylphenyl)-1,4-dithiepin-1,1,4,4-tetroxide (20) (see Fig. 1), but there is only one nonpeptide galanin receptor ligand, galnon, that shows agonist activity (21).In this study, we report an example of a nonpeptide subtype selective agonist for the galanin receptor, galmic, discovered by application of a combinatorial library approach (22). MethodsExperimental. Reactions were performed under an argon atmosphere, NMR spectra were recorded on a Bruker DRX 600 spectrometer (unless otherwise mentioned), and the chemical shifts are given in ppm relative to tetramethylsilane. The spectra were referenced to deuterated solvents indicated in brackets in the analytical data. High-resolution MALDI-Fourier transform MS (FTMS) measurements were performed on an IonSPec (Lake Forest, CA) FTMS mass spectrometer by using 2,5-dihydroxybenzoic acid as the matrix. For TLC, silica plates IB2-F (J. T. Baker) were used. For column chromatography, silica gel 60, 230-400 mesh (Merck) was used. Preparative chromatographic plates and silica gel 60 F 254 (20 ϫ 20 cm, 0.5 mm) were used. Anhydrous solvents and chemicals were used as purchased from commercial suppliers. General Procedures. ...

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Antidepressants

Glennon¹,

Iversen²

2010

Burger's Medicinal Chemistry and Drug Discovery

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This chapter reviews the antidepressant drugs currently available in Europe and/or the United States from the perspectives of their clinical efficacy, pharmacokinetics, pharmacology, structure–activity relationships, metabolism, and mechanisms of action. The older nonselective monoamine oxidase inhibitors (e.g., phenelzine, tranylcypromine) have largely been replaced by agents that selectively inhibit monoamine oxidase A (e.g., moclobemide) or by inhibitors of norepinephrine/serotonin monoamine transporter reuptake mechanisms. The first generation of such drugs, the tricyclic antidepressants, suffered from a number of dangerous and unpleasant adverse side effects caused by their many other pharmacological actions on the heart and on cholinergic and other monoamine receptors in the brain. Most of the current generation of antidepressants are serotonin‐selective reuptake inhibitors or mixed norepinephrine/serotonin reuptake inhibitors that possess a safer side‐effect profile. These drugs have gained widespread use in the treatment of depression and a number of related psychiatric conditions, including phobias and the treatment of generalized anxiety disorder (GAD). Some agents that act as norepinephrine‐selective reuptake inhibitors (e.g., reboxetine) are also clinically effective and there is considerable overlap between noradrenergic and serotonergic mechanisms in the CNS. Monoamine selectivity can also be altered by the formation of active metabolites in vivo . All antidepressants require several weeks of treatment before the maximum clinical benefit is seen. This may be attributable to drug‐induced alterations in the expression of receptors in brain (e.g., downregulation of 5‐HT 1A receptors) and/or alterations in the expression of neurotrophic factors (e.g., brain‐derived neurotrophic factor, vascular endothelial growth factor) associated with changes in neurogenesis in certain brain regions. New approaches to future antidepressant drug discovery include antagonists for glutamate NMDA receptors, substance P NK1 receptors, corticotrophin releasing factor receptors, or agonists/antagonists for galanin receptors.

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Galmic, a nonpeptide galanin receptor agonist, affects behaviors in seizure, pain, and forced-swim tests

Cited by 134 publications

References 33 publications

GalR2-positive allosteric modulator exhibits anticonvulsant effects in animal models

GalR2-positive allosteric modulator exhibits anticonvulsant effects in animal models

Synthesis of galmic: A nonpeptide galanin receptor agonist

Antidepressants

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