[Phe4]somatostatin: a potent, selective inhibitor of growth hormone release.

Meyers, Chester A.; Coy, David H.; Murphy, William A.; Redding, Tommie W.; Arimura, Akira

doi:10.1073/pnas.77.1.577

Cited by 26 publications

(7 citation statements)

References 9 publications

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“…Better evidence for dissociation between pituitary and cortex SRIF recep tors is obtained by competition with several synthetic SRIF analogs. Substitution of D-5-F-Trp and D-5-Br-Trp for the Trp8 residue results in potent pituitary SRIF agonists [18]. However, only the fluorinated analog exhibits such en hanced competition (32 times more potent than SRIF) for SRIF binding to cortex membranes [35].…”

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confidence: 99%

Differential Binding of Somatostatin Agonists to Somatostatin Receptors in Brain and Adenohypophysis

Heiman

Murphy

Coy³

1987

Neuroendocrinology

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In order to improve our understanding of the ligand specificity of somatostatin (SRIF) receptors in pituitary and brain, and to identify analogs that bind to one type exclusively, we compared several new SRIF analogs for competitive binding to pituitary and cerebral cortex membranes. Binding of [¹²⁵I-Tyr¹¹]SRIF to hypophysis and brain was of high affinity [KD = 0.76 nM (0.2–1.3) and 0.37 nM (0.1–0.8), mean (95% confidence limits)] and was characteristic of binding to one class of sites in both tissues. Competition by several SRIF analogs for such radioligand binding demonstrated that ligand specificity of adenohypophysial receptors was distinctly different from that of cerebral cortex. Two cyclic octapeptides D-Phe-Cys-Tyr-D-Trp-Lys-Val-Cys-Thr-NH₂ and D-Nal-Cys-Tyr-D-Trp-Lys-Val-Cys-Thr-NH₂ bound to pituitary SRIF receptors with high affinity [Ki = 0.85 nM (0.5–1.2) and 0.35 nM (-0.3–0.9)] and were potent inhibitors of GH secretion from primary cultured pituitary cells [EC₅₀ = 0.009 nM (0–0.02) and 0.017 nM (0.01–0.02), respectively]. However, these selective peptides did not compete (Ki ≧1 µM) for radioligand binding to brain. Amidation of the C-terminal end appeared to strikingly alter brain SRIF receptor recognition of the substituted ligand. Indeed, such amidation of the parent peptide, D-Phe-Cys-Phe-D-Trp-Lys-Thr-Cys-Thr-OL (SMS 201–995) resulted in a reduced ability to displace labeled ligand from brain sites [Ki= 165.3 nM (47.6–282.9) to 842.2 nM (603.9–1,081)] but did not affect competition for pituitary receptors. Our results indicate that anterior pituitary SRIF receptors (SRIF_a) have ligand specificities which are clearly different from those of their brain counterparts (SRIFa). Further, we have identified two potent SRIF_a agonists which could be key ligands for studying interactions at the SRIF_a receptor as well as being useful selective therapeutic agents

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mentioning

confidence: 99%

Differential Binding of Somatostatin Agonists to Somatostatin Receptors in Brain and Adenohypophysis

Heiman

Murphy

Coy³

1987

Neuroendocrinology

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“…Murphy, Redding, Arimura and Schally 1980) and [D-5Br-Trp 8 , D-Cys 14 ]-SRIF {Hirst, Show, Meyers and Coy 1980) were reported to be specific for GH suppression.…”

Section: Discussionmentioning

confidence: 94%

Development of Specific and Non-Specific Somatostatin Analogs

Nakano¹,

Harano²,

Emura³

et al. 1986

Horm Metab Res

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Biological activity of six somatostatin analogs has been investigated. In these analogs, disulfide bond is replaced by ethylene bond cyclized with alpha-amino suberic acid. In addition, they contain unique D-configuration in both Trp8 and Cys14 moiety with dicarba substitution. An analog of the short chain length, C omega 7-cyclo (Phe6-Phe7-D-Trp8-Lys9-Thr10-Phe11-D-Asu14) (analog 4) has suppressive effect for GH, but not for other hormones. Analog 6, C omega 9-cyclo(Asn5-Phe6-Phe7-D-Trp8-Lys9-Thr10-Ph e11-Thr12-D-Asu14), has suppressed GH and insulin secretion, but not for gastrin and glucagon. Analog 1, C omega 11-cyclo (Lys4-Asn5-Phe6-Phe7-D-Trp8-Lys9-Thr10-Phe11- Thr12-Ser13-D-Asu14] and 5, C omega 9-cyclo (Lys4-Asn5-Phe6-Phe7-D-Trp8-Lys9-Thr10-Phe11-D-+ ++Asu14) have broad suppressive effect for GH, gastrin, insulin and glucagon release after arginine infusion. The shortest analog, analog 2, C omega 5-cyclo (Phe7-D-Trp8-Lys9-Thr10-D-Asu14) has weak suppressive effect of GH, insulin and glucagon secretion, and it is suggested that Phe6 and Phe11 are necessary for the appearance of suppressive effect of GH. Specific analog, analog 4, may be useful for the future treatment for acromegaly and diabetic retinopathy. Nonspecific analogs, 1 and 5 are candidates for the clinical application of wide variety.

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“…Murphy et al (30,31) have shown that alteration of Lys4 results in analogs with selective inhibition of growth hormone release. The importance of Lys4 seems to be shared by both intestinal ion transport properties and inhibition of the release of growth hormones.…”

Section: Discussionmentioning

confidence: 99%

Structure-Activity Relationships of Somatostatin Analogs in the Rabbit Ileum and the Rat Colon

Rosenthal¹,

Yamashiro²,

Rivier³

et al. 1983

J. Clin. Invest.

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A B S T R A C T Somatostatin increases absorption of electrolytes and inhibits diarrhea in patients with endocrine tumors and short bowel syndrome. In an attempt to develop a gut-specific somatostatin analog, each amino acid in the somatostatin molecule was replaced with L-alanine, deleted, or substituted with its D-isomer. The potency of each analog to stimulate ion transport in the rabbit ileum was then determined using the modified Ussing chamber technique. The results were compared to the ability of each analog to inhibit the stimulated release of growth hormone from cultured rat anterior pituitary cells and to inhibit the arginine-stimulated release of insulin and glucagon in the rat in vivo. Analogs that showed gut selectivity were then tested for their ion transport properties in the rat colon. Results: (a) Substitution with L-alanine or deletion of the amino acid at position 6, 7, 8, or 9 and deletion of Threonine'°-produced analogs with significantly reduced ion transport properties to <4% of somatostatin's action. The substitution also markedly reduced the ability of the compounds to inhibit the release of growth hormone, insulin, and glucagon. (b) Selectivity of intestinal ion transport was achieved by any one of the following alterations: L-alanine substitution at Phenylalanine", deletion of Phenylalanine", substitution with D-lysine at Lysine4, or substitution with L-alanine at Lysine4. These compounds had intestinal ion transport properties of 52, 34, 139, and 94%, respectively, while demonstrating little or

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[Phe4]somatostatin: a potent, selective inhibitor of growth hormone release.

Cited by 26 publications

References 9 publications

Differential Binding of Somatostatin Agonists to Somatostatin Receptors in Brain and Adenohypophysis

Differential Binding of Somatostatin Agonists to Somatostatin Receptors in Brain and Adenohypophysis

Development of Specific and Non-Specific Somatostatin Analogs

Structure-Activity Relationships of Somatostatin Analogs in the Rabbit Ileum and the Rat Colon

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