Small molecule somatostatin receptor subtype-2 antagonists

Hay, Bruce A.; Cole, Bridget M.; DiCapua, Frank M.; Kirk, Glen W.; Murray, Marianne C.; Nardone, Rona A.; Pelletier, Dennis; Ricketts, A. P.; Robertson, Alan S.; Siegel, Todd W.

doi:10.1016/s0960-894x(01)00568-6

Cited by 12 publications

(8 citation statements)

References 18 publications

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“…Cortistatin-14, SRIF-28 and synthetic analogues of SRIF were also tested for their ability to increase intracellular Ca 2 þ via the human sst 2 receptor ( Figure 2a, Table 1). In general, compounds that are reported to be predominantly sst 2 selective (BIM 23027, L 363,301, compound 6 (Raynor et al, 1993;Hay et al, 2001a)), as well as those that are equally sst 2 and sst 5 selective ([Tyr 3 ]octreotide, octreotide, RC 160; (Hannon et al, 2002)) acted as full agonists (with the exception of the nonpeptide compound 6) and displayed high potencies that were similar to those of natural ligands and analogues (SRIF-14, SRIF-28, LTT-SRIF-28). CGP 23996 and cortistatin-14 had somewhat lower potency compared to the other analogues, whereas the predominantly sst 5 selective compounds (L 362,855, BIM 23052;(Hannon et al, 2002)) as well as the two isoforms of the putative sst 2 -selective antagonist CYN 154806 were less potent and acted as partial agonists.…”

Section: Resultsmentioning

confidence: 99%

Comparison of functional profiles at human recombinant somatostatin sst₂ receptor: simultaneous determination of intracellular Ca²⁺ and luciferase expression in CHO‐K1 cells

Nunn

Cervia

Langenegger

et al. 2004

British J Pharmacology

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1 Somatostatin (somatotropin release inhibiting factor; SRIF) acts via five G protein-coupled receptors (sst 1 -sst 5 ) that modulate multiple cellular effectors. The aim of this study was to compare two functional effects of the human sst 2 receptor stably expressed in CHO-K1 cells in a single experiment using a duplex assay for intracellular calcium and serum response element (SRE)-driven luciferase expression. 2 Intracellular calcium was measured using a fluorometric imaging plate reader II (FLIPR II). SRIF-14 rapidly and transiently increased intracellular calcium with a pEC 50 of 8.7470.03 (n ¼ 52). At 5 h after FLIPR II measurements, luciferase expression was determined. SRIF-14 concentrationdependently increased luciferase expression (pEC 50 ¼ 9.0670.03, n ¼ 52). 3 Natural and synthetic agonist/antagonist ligands for SRIF receptors were tested in the duplex assay. Correlation of agonist potencies and efficacies between the two responses were significant (r 2 ¼ 0.83 and 0.90, pEC 50 and E max , respectively). 4 Pertussis toxin pretreatment reduced SRIF-14/octreotide-mediated intracellular calcium increases by 45-47% and luciferase expression by 95-98%. 5 Thapsigargin pretreatment abolished the SRIF-14/octreotide-mediated intracellular calcium increase but had no effect on luciferase expression. 6 In conclusion, SRIF stimulates an increase in intracellular calcium and SRE-luciferase expression via human sst 2 receptors in CHO-K1 cells.

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Section: Resultsmentioning

confidence: 99%

Comparison of functional profiles at human recombinant somatostatin sst₂ receptor: simultaneous determination of intracellular Ca²⁺ and luciferase expression in CHO‐K1 cells

Nunn

Cervia

Langenegger

et al. 2004

British J Pharmacology

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“…At present, very few SRIF analogues have been shown to exhibit antagonistic activity with receptor subtype selectivity (Hay et al ., 2001; Poitout et al ., 2001; Cervia et al ., 2002b; Hannon et al ., 2002a). In addition, depending on the tissue type and receptor coupling efficiency, ‘antagonists’ may show agonism.…”

Section: Discussionmentioning

confidence: 99%

“…SRIF‐14 and SRIF‐28 were purchased from Bachem AG (Bubendorf, Switzerland). CH‐275, octreotide, Tyr 3 ‐octreotide, BIM 23027, L ‐363,301, L ‐362,855, D ‐Tyr 8 CYN 154806 (Feuerbach et al ., 2000; Nunn et al ., 2002), L ‐797,591, L ‐796,778 (Rohrer et al ., 1998), NNC 26‐9100 (Liu et al ., 1998), compounds 1–4 (Nunn et al ., 2003b), compounds 6, 7a and 7e (Hay et al ., 2001), SRA 880 (Hoyer et al ., 2002), compound 4k (Poitout et al ., 2001) were synthesised at Novartis Pharma AG (Basel, Switzerland). L ‐803,087 and L ‐817,818 (Rohrer et al ., 1998) were kindly provided by Merck Research Laboratories (Rahway, NJ, U.S.A.).…”

Section: Methodsmentioning

confidence: 99%

Pharmacological characterisation of native somatostatin receptors in AtT‐20 mouse tumour corticotrophs

Cervia

Nunn

Fehlmann

et al. 2003

British J Pharmacology

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1 The mouse corticotroph tumour cell line AtT-20 is a useful model to investigate the physiological role of native somatostatin (SRIF, Somatotropin release inhibitory factor) receptor subtypes (sst 1 -sst 5 ). The objective of this study was to characterise the pharmacological features and the functional effects of SRIF receptors expressed by 4 SRIF analogues inhibited the forskolin-stimulated cAMP levels depending on concentration. sst 2/5 receptor-selective ligands were highly potent, whereas sst 1/3/4 receptor-selective ligands had no significant effects. The sst 2 receptor antagonist D-Tyr 8 -CYN 154806 competitively antagonised the effects of SRIF-14 and sst 2 receptor-preferring agonists, but not those of L-817,818. 5 The complex binding properties of SRIF receptor analogues indicate that sst 2 and sst 5 receptors are the predominant SRIF receptors expressed on AtT-20 cell membranes with no or only negligible presence of sst 1 , sst 3 and sst 4 receptors. In the functional studies using cAMP accumulation, only sst 2 and sst 5 receptors appear to play a role. However, the 'predominant' receptor appears to be the sst 2 receptor, although sst 5 receptors can also mediate the effect, when the ligand is not able to activate sst 2 receptors. This clearly adds flexibility to SRIF-mediated functional effects and suggests that the physiological role of SRIF and its analogues may be mediated preferentially via one subtype over another.

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“…This is consistent with the previously reported sst 2 selectivity of a biphenyl-4-carboxamide-substituted mimetic. 17 A shortened version of 3, analogue 10f, was prepared. Compared to 3, binding affinities toward sst 1,2,3 decreased.…”

Section: Discussionmentioning

confidence: 99%

Highly Potent 4-Amino-indolo[2,3-c]azepin-3-one-Containing Somatostatin Mimetics with a Range of sst Receptor Selectivities

et al. 2008

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The synthesis, biological evaluation, and conformational analysis of 4-amino-indolo[2,3-c]azepin-3-one (Aia)-containing SRIF mimetics are reported. Different subtype selectivities are observed depending on the N- and C-terminal substituents of the D-Aia-Lys dipeptide mimetic. An sst(5)-selective analogue with subnanomolar binding affinity was obtained that is the most potent agonist reported to date. A nonselective mimetic with high potency was also identified. This study allows a better definition of the bioactive conformation of the essential D-Trp side chain in the somatostatin pharmacophore.

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Small molecule somatostatin receptor subtype-2 antagonists

Cited by 12 publications

References 18 publications

Comparison of functional profiles at human recombinant somatostatin sst₂ receptor: simultaneous determination of intracellular Ca²⁺ and luciferase expression in CHO‐K1 cells

Comparison of functional profiles at human recombinant somatostatin sst₂ receptor: simultaneous determination of intracellular Ca²⁺ and luciferase expression in CHO‐K1 cells

Pharmacological characterisation of native somatostatin receptors in AtT‐20 mouse tumour corticotrophs

Highly Potent 4-Amino-indolo[2,3-c]azepin-3-one-Containing Somatostatin Mimetics with a Range of sst Receptor Selectivities

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Small molecule somatostatin receptor subtype-2 antagonists

Cited by 12 publications

References 18 publications

Comparison of functional profiles at human recombinant somatostatin sst2 receptor: simultaneous determination of intracellular Ca2+ and luciferase expression in CHO‐K1 cells

Comparison of functional profiles at human recombinant somatostatin sst2 receptor: simultaneous determination of intracellular Ca2+ and luciferase expression in CHO‐K1 cells

Pharmacological characterisation of native somatostatin receptors in AtT‐20 mouse tumour corticotrophs

Highly Potent 4-Amino-indolo[2,3-c]azepin-3-one-Containing Somatostatin Mimetics with a Range of sst Receptor Selectivities

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Comparison of functional profiles at human recombinant somatostatin sst₂ receptor: simultaneous determination of intracellular Ca²⁺ and luciferase expression in CHO‐K1 cells

Comparison of functional profiles at human recombinant somatostatin sst₂ receptor: simultaneous determination of intracellular Ca²⁺ and luciferase expression in CHO‐K1 cells