Spiro[1<i>H</i>-indene-1,4‘-piperidine] Derivatives As Potent and Selective Non-Peptide Human Somatostatin Receptor Subtype 2 (sst<sub>2</sub>) Agonists

Lu, Yang; Guo, Liangqin; Pasternak, Alexander; Mosley, Ralph T.; Rohrer, Susan P.; Birzin, Elizabeth T.; Foor, Forrest; Cheng, Kang; Schaeffer, James M.; Patchett, Arthur A.

doi:10.1021/jm980194h

Cited by 57 publications

(47 citation statements)

References 30 publications

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“…In accord with its method of selection, the potency of compound 1 was increased by resolution and by extending the amine chain length to that of Lys in the D-Trp analog 2 (40). Completion of the Lys structure as its methyl ester 3 provided both high affinity and selectivity for sst2.…”

Section: Resultsmentioning

confidence: 99%

Synthesis and biological activities of potent peptidomimetics selective for somatostatin receptor subtype 2

Berk²,

Rohrer³

et al. 1998

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

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131

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A series of nonpeptide somatostatin agonists which bind selectively and with high affinity to somatostatin receptor subtype 2 (sst2) have been synthesized. One of these compounds, L-054,522, binds to human sst2 with an apparent dissociation constant of 0.01 nM and at least 3,000-fold selectivity when evaluated against the other somatostatin receptors. L-054,522 is a full agonist based on its inhibition of forskolin-stimulated adenylate cyclase activity in Chinese hamster ovary-K1 cells stably expressing sst2. L-054,522 has a potent inhibitory effect on growth hormone release from rat primary pituitary cells and glucagon release from isolated mouse pancreatic islets. Intravenous infusion of L-054,522 to rats at 50 g/kg per hr causes a rapid and sustained reduction in growth hormone to basal levels. The high potency and selectivity of L-054,522 for sst2 will make it a useful tool to further characterize the physiological functions of this receptor subtype.Somatostatin is widely distributed throughout the central nervous system and various endocrine tissues (1-3). Two biologically active forms of somatostatin are known, a 14-amino acid peptide and an N-terminal extended peptide with 28 amino acids (4 -6). Somatostatin has multiple functions, including modulation of growth hormone, insulin, glucagon, and gastric acid secretion (3, 7-10). Five somatostatin receptors (sst1-5) have been cloned and characterized (11)(12)(13)(14). All five receptors are members of the G protein-linked receptor family (15). Structure-function studies with a large number of peptidal analogs have shown that the Trp 8 -Lys 9 dipeptide of somatostatin is necessary for high-affinity binding (16) and have facilitated the development of potent analogs, including SMS 201-955 (Sandostatin or octreotide) which is clinically used for the treatment of acromegaly and certain endocrine tumors (17-19). We describe here strategies that were successful in designing small molecule subtype 2-selective agonists whose potencies on this receptor exceed somatostatin. Studies utilizing one of these subtype-selective somatostatin peptidomimetics, L-054,522, in both in vivo and in vitro experiments demonstate that somatostatin receptor subtype 2 (sst2) mediates the inhibition of growth hormone release from the rat anterior pituitary as well as glucagon from the rat pancreas. Insulin release is only inhibited at significantly higher concentrations of the compound. These results suggest possible therapeutic applications of selective sst2 agonists. Compound 4 was initially synthesized in a combinatorial library consisting of 20 diamines, 20 amino acids, and 79 amines. The diamines were linked to 4-(4-hydroxymethyl-3-methoxyphenoxy)butyric acid functionalized Tentagel resin via urethane chemistry in a regiorandom way. 9-Fluorenylmethoxycarbonyl amino acids were coupled to the amine resins using standard 1,3-diisopropylcarbodiimide coupling. The 9-fluorenylmethoxycarbonyl groups were removed with piperidine and activated with p-nitrophenyl chloroformate before ...

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Section: Resultsmentioning

confidence: 99%

Synthesis and biological activities of potent peptidomimetics selective for somatostatin receptor subtype 2

Berk²,

Rohrer³

et al. 1998

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

Self Cite

131

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“…Finally, as compared with the dose-related inhibition of GH secretion obtained with the sst2-D2DR dihybrid, BIM-23A387, or with a combination of compounds targeting individual sst2, sst5, and D2DR receptors, the trihybrids, BIM-23A760 and BIM-23A761, produced the greatest maximal GH inhibition [42]. An increase in sst2 binding affinity has been previously achieved with a nonpeptide selective agonist, L-054522, which binds to the human sst2 receptor with a reported Ki of 10 pmol/L [43]. High binding affinity for sst2 is apparently a key point in the higher efficacy of the dopastatin compounds.…”

Section: The Dopamine-somatostatin Hybrid Molecules In Pituitary Adenmentioning

confidence: 88%

Somatostatin–dopamine ligands in the treatment of pituitary adenomas

Saveanu

Jaquet

2008

Rev Endocr Metab Disord

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Somatostatin receptors (sst1-5) and dopamine receptor 2 (D2DR) are well expressed and co-localized in several human pituitary adenomas, suggesting possible functional interactions in the control of hormonal hypersecretion and tumor cell growth. The present review describes the expression and functionality of these receptors in the different classes of human pituitary adenomas. The sst2 agonists, octreotide and lanreotide, control GH hypersecretion and tumor growth in about 65% of somatotropinomas. The D2DR agonists, bromocriptine and cabergoline, control about 90% of prolactinomas. Such drugs are much less effective in the control of the others pituitary adenomas also expressing ssts and D2DR receptors. The second part summarizes the current knowledge on new chimeric compounds with sst2, sst5, and D2DR affinity. Such ligands bearing distinct ssts and DRD2 pharmacophores may synergistically produce an increased control of secretion and/or of proliferation in the different types of pituitary adenomas. The mechanisms of action of such chimeric molecules through increased binding affinities, prolonged bioavailability, ligand-induced modulation of receptors heterodimerization, are discussed.

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“…Finally, the most potent sstr2-interacting chimeric molecules produced the greatest maximal GH inhibition. An increase in sstr2-binding affinity has previously been achieved with a non-peptide selective agonist, L-054522, which binds to the human sstr2 with a reported K i of 0.01 nmol/l (19). High binding affinity for sstr2 is apparently a key point in the higher efficacy of the chimeric compounds; however, it does not completely explain the greater GH-suppressing efficacy of the new chimeric compounds since, among our compounds, BIM-23A765, despite its high affinity for sstr2, did not suppress GH secretion more efficiently than octreotide.…”

Section: Discussionmentioning

confidence: 99%

Efficacy of chimeric molecules directed towards multiple somatostatin and dopamine receptors on inhibition of GH and prolactin secretion from GH-secreting pituitary adenomas classified as partially responsive to somatostatin analog therapy

Jaquet¹,

Gunz²,

Saveanu³

et al. 2005

eur j endocrinol

135

109

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Objective: This study compared the potency of a somatostatin receptor (sstr)2 -sstr5 analog, BIM-23244, of an sstr2-dopamine D2 receptor (sstr2-DAD2) molecule, BIM-23A387 and of new somatostatin-dopamine chimeric molecules with differing, enhanced affinities for sstr2, sstr5 and DAD2, BIM-23A758, BIM-23A760 and BIM-23A761, to suppress GH and prolactin (PRL) from 18 human GH adenomas that are partially responsive to octreotide or lanreotide. Materials and methods: The sstr2, sstr5 and DAD2 mRNA levels were determined by RT-PCR. The effect of drugs was tested in cell cultures at various concentrations. Results: In all tumors, the sstr2, sstr5 and DAD2 mRNA levels were coexpressed (mean levels^S.E.M. 0.4^0.1, 5.3^1.9 and 2.0^0.4 copy/copy b-glucuronidase). In 13 tumors, the maximal suppression of GH secretion produced by BIM-23A387 (30^3%) and BIM-23244 (28^3%) was greater than that produced by octreotide (23^3%). In six out of 13 tumors, BIM-23A758, BIM-23A760 and BIM-23A761 produced greater maximal suppression of GH secretion than octreotide (33^5, 38^2 and 41^2 vs 24^2%). Their EC 50 values were 10, 2 and 4 pmol/l. BIM-23A761 was more effective than BIM-23A387 in GH suppression (41^2 vs 32^4%). The new chimeric molecules produced maximal PRL suppression greater than octreotide (62^8 to 74^5 vs 46^11%). Conclusions: Novel dopamine-somatostatin chimeric molecules with differing, enhanced activity at sstr2, sstr5 and DAD2, consistently produced significatly greater suppression of GH and PRL than either octreotide or single-receptor-interacting ligands in tumors from patients classified as only partially responsive to octreotide therapy. The higher efficacy of the chimeric compounds was, at least partially, linked to their high affinity for sstr2 (IC 50 1-10 pmol/l). The other mechanisms by which such molecules produce an enhanced inhibition of GH remain to be elucidated.

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Spiro[1H-indene-1,4‘-piperidine] Derivatives As Potent and Selective Non-Peptide Human Somatostatin Receptor Subtype 2 (sst₂) Agonists

Cited by 57 publications

References 30 publications

Synthesis and biological activities of potent peptidomimetics selective for somatostatin receptor subtype 2

Synthesis and biological activities of potent peptidomimetics selective for somatostatin receptor subtype 2

Somatostatin–dopamine ligands in the treatment of pituitary adenomas

Efficacy of chimeric molecules directed towards multiple somatostatin and dopamine receptors on inhibition of GH and prolactin secretion from GH-secreting pituitary adenomas classified as partially responsive to somatostatin analog therapy

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Spiro[1H-indene-1,4‘-piperidine] Derivatives As Potent and Selective Non-Peptide Human Somatostatin Receptor Subtype 2 (sst2) Agonists

Cited by 57 publications

References 30 publications

Synthesis and biological activities of potent peptidomimetics selective for somatostatin receptor subtype 2

Synthesis and biological activities of potent peptidomimetics selective for somatostatin receptor subtype 2

Somatostatin–dopamine ligands in the treatment of pituitary adenomas

Efficacy of chimeric molecules directed towards multiple somatostatin and dopamine receptors on inhibition of GH and prolactin secretion from GH-secreting pituitary adenomas classified as partially responsive to somatostatin analog therapy

Contact Info

Product

Resources

About

Spiro[1H-indene-1,4‘-piperidine] Derivatives As Potent and Selective Non-Peptide Human Somatostatin Receptor Subtype 2 (sst₂) Agonists