SRA880, in vitro characterization of the first non-peptide somatostatin sst1 receptor antagonist

Hoyer, Daniel; Nunn, Caroline; Hannon, Jason P.; Schoeffter, Philippe; Feuerbach, Dominik; Schuepbach, E.; Langenegger, Daniel; Bouhelal, Rochdi; Hurth, Konstanze; Neumann, Peter; Troxler, Thomas; Pfaeffli, P.

doi:10.1016/j.neulet.2004.02.017

Cited by 34 publications

(9 citation statements)

References 16 publications

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“…SRA880 is the first reported nonpeptide SRIF SST 1 competitive antagonist, with high affinity for both native and recombinantly expressed SST 1 from various species ( Fig. 6 ; Table 4 ) (rat, mouse, monkey, human), while displaying low affinity for a range of other neurotransmitter receptors, except the dopamine receptor D4 ( Hoyer et al, 2004 ). The compound is bioavailable and brain penetrant.…”

Section: Somatostatin Receptormentioning

confidence: 99%

International Union of Basic and Clinical Pharmacology. CV. Somatostatin Receptors: Structure, Function, Ligands, and New Nomenclature

et al. 2018

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Somatostatin, also known as somatotropin-release inhibitory factor, is a cyclopeptide that exerts potent inhibitory actions on hormone secretion and neuronal excitability. Its physiologic functions are mediated by five G protein–coupled receptors (GPCRs) called somatostatin receptor (SST)1–5. These five receptors share common structural features and signaling mechanisms but differ in their cellular and subcellular localization and mode of regulation. SST2 and SST5 receptors have evolved as primary targets for pharmacological treatment of pituitary adenomas and neuroendocrine tumors. In addition, SST2 is a prototypical GPCR for the development of peptide-based radiopharmaceuticals for diagnostic and therapeutic interventions. This review article summarizes findings published in the last 25 years on the physiology, pharmacology, and clinical applications related to SSTs. We also discuss potential future developments and propose a new nomenclature.

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Section: Somatostatin Receptormentioning

confidence: 99%

International Union of Basic and Clinical Pharmacology. CV. Somatostatin Receptors: Structure, Function, Ligands, and New Nomenclature

et al. 2018

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“…An example is BIM-23A760, which accelerates the suppression of growth hormone and adrenocorticotropic hormone by the interaction with Sst 2 and Drd2 simultaneously; (3) Chimeric-somatostatin vaccinations (Haffer, 2012): a fusion protein expressing chloramphenicol acetyl transferase protein and somatostatin. Two somatostatin vaccinations, JH17 and JH18, can effectively reduce weight gain and reduce final body weight percentage of normal, non-obese mice and mice with diet-induced obesity via the intra-peritoneal route; (4) Non-peptide antagonists, such as SRA880 (Sst 1 selective), ACQ090 (Sst 3 selective) and Sst 4 selective β peptide agonists (Rivier et al, 2003; Hoyer et al, 2004). Despite this extensive list, the practical use of somatostatin in the brain is hampered by the multiple effects of the peptide, by the need for small molecules targeting specific, high affinity receptors on the target cells in specific brain regions, and by the need for feasible routes of administration that lead to fast delivery into the brain.…”

Section: Somatostatin: Genes Neurons and Pharmacologymentioning

confidence: 99%

Reduced brain somatostatin in mood disorders: a common pathophysiological substrate and drug target?

2013

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Our knowledge of the pathophysiology of affect dysregulation has progressively increased, but the pharmacological treatments remain inadequate. Here, we summarize the current literature on deficits in somatostatin, an inhibitory modulatory neuropeptide, in major depression and other neurological disorders that also include mood disturbances. We focus on direct evidence in the human postmortem brain, and review rodent genetic and pharmacological studies probing the role of the somatostatin system in relation to mood. We also briefly go over pharmacological developments targeting the somatostatin system in peripheral organs and discuss the challenges of targeting the brain somatostatin system. Finally, the fact that somatostatin deficits are frequently observed across neurological disorders suggests a selective cellular vulnerability of somatostatin-expressing neurons. Potential cell intrinsic factors mediating those changes are discussed, including nitric oxide induced oxidative stress, mitochondrial dysfunction, high inflammatory response, high demand for neurotrophic environment, and overall aging processes. Together, based on the co-localization of somatostatin with gamma-aminobutyric acid (GABA), its presence in dendritic-targeting GABA neuron subtypes, and its temporal-specific function, we discuss the possibility that deficits in somatostatin play a central role in cortical local inhibitory circuit deficits leading to abnormal corticolimbic network activity and clinical mood symptoms across neurological disorders.

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“…Somatostatins are peptides that exist in the brain in two main forms: somatostatin-14 (a tetradecapeptide) and somatostatin-28 (an amino-terminally extended octacosapeptide; (Hoyer et al, 1995; Hoyer et al, 2004). Somatostatin inhibits the release of a variety of pituitary hormones and plays a role as a neurotransmitter in the central nervous system (Patel, 1999; Bissette, 2001).…”

Section: Introductionmentioning

confidence: 99%

“…Somatostatin-28 was selected for the present studies because it is a more stable compound and has a longer plasma half-life than somatostatin-14 (Patel, 1999). Additionally, we evaluated the effects of SRA-880 ([3R,4aR,10aR]-1,2,3,4,4a,5,10,10a-octahydro-6-methoxy-1-methyl-benz[g] quinoline-3-carboxylic-acid-4-(4-nitro-phenyl)-piperazine-amide, hydrogen malonate), a nonpeptide sst 1 receptor antagonist (Hoyer et al, 2004), on PPI and brain reward function in the ICSS procedure. SRA-880 was selected to be used in these studies as one of the first non-peptide receptor antagonists available for basic science investigations.…”

Section: Introductionmentioning

confidence: 99%

Somatostatin-28 modulates prepulse inhibition of the acoustic startle response, reward processes and spontaneous locomotor activity in rats

et al. 2010

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Somatostatins have been shown to be involved in the pathophysiology of motor and affective disorders, as well as psychiatry disorders, including schizophrenia. We hypothesized that in addition to motor function, somatostatin may be involved in somatosensory gating and reward processes that have been shown to be dysregulated in schizophrenia. Accordingly, we evaluated the effects of intracerebroventricular administration of somatostatin-28 on spontaneous locomotor and exploratory behavior measured in a behavioral pattern monitor, sensorimotor gating, prepulse inhibition (PPI) of the acoustic startle reflex, and brain reward function (measured in a discrete trial intracranial self-stimulation procedure) in rats. Somatostatin-28 decreased spontaneous locomotor activity during the first 10 min of a 60 min testing session with no apparent changes in the exploratory activity of rats. The highest somatostatin-28 dose (10 μg/5 μl/side) induced PPI deficits with no effect on the acoustic startle response or startle response habituation. The somatostatin-induced PPI deficit was partially reversed by administration of SRA-880, a selective somatostatin 1 (sst1) receptor antagonist. Somatostatin-28 also induced elevations in brain reward thresholds, reflecting an anhedonic-like state. SRA-880 had no effect on brain reward function under baseline conditions. Altogether these findings suggest that somatostatin-28 modulates PPI and brain reward function but does not have a robust effect on spontaneous exploratory activity. Thus, increases in somatostatin transmission may represent one of the neurochemical mechanisms underlying anhedonia, one of the negative symptoms of schizophrenia, and sensorimotor gating deficits associated with cognitive impairments in schizophrenia patients.

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SRA880, in vitro characterization of the first non-peptide somatostatin sst1 receptor antagonist

Cited by 34 publications

References 16 publications

International Union of Basic and Clinical Pharmacology. CV. Somatostatin Receptors: Structure, Function, Ligands, and New Nomenclature

International Union of Basic and Clinical Pharmacology. CV. Somatostatin Receptors: Structure, Function, Ligands, and New Nomenclature

Reduced brain somatostatin in mood disorders: a common pathophysiological substrate and drug target?

Somatostatin-28 modulates prepulse inhibition of the acoustic startle response, reward processes and spontaneous locomotor activity in rats

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